Renal excretion is an important clearance pathway for many drugs and their metabolites. Impaired renal excretion, either as a result of kidney disease or the effects of co-administered drugs, can lead to accumulation of drugs and their metabolites. In many cases dosing adjustments are required to maintain optimal therapeutic effects and to avoid accumulation of drugs to toxic levels. In this chapter, the processes involved in renal drug disposition are described, and current knowledge of the role of transport proteins in renal drug secretion and reabsorption is reviewed. Special attention is given to the effect of renal drug–drug interactions and renal insufficiency on pharmacokinetics and to dosing adjustments that are required in the setting of renal dysfunction.
renal pharmacokinetics, renal drug-drug interactions, membrane transporters, renal insufficiency, drug dosing
Numerous drugs are eliminated by the kidney. For others, polar metabolites are formed by metabolism or conjugation (usually in the liver)—that are then excreted by the kidney. Renal impairment thereby leads to the accumulation of drugs and their metabolites. For many drugs, doses must be adjusted to attain concentrations similar to those obtained in patients with normal renal function. Renal dysfunction can also affect distribution of drugs, primarily by effects on protein binding. Last, changes in renal function can affect response to drugs independent of any change in disposition.
Several general characteristics of a drug allow prediction as to whether renal dysfunction is likely to affect its disposition sufficiently to mandate changes in drug dosing ( Table 95.1 ). If a drug has a wide therapeutic index, accumulation in patients with renal insufficiency to concentrations several-fold higher than in patients with normal renal function has little, if any, consequence, and dose adjustment can be ignored. For example, a number of penicillin derivatives and many cephalosporins are primarily eliminated by the kidney but can accumulate with little risk. Toxic accumulation of these drugs can sometimes occur, but usually only with massive doses in patients with compromised excretion.
|Therapeutic index||If the drug has a wide therapeutic index, its accumulation poses negligible risk.|
|Protein binding||A high degree of binding (>90%) to albumin makes displacement likely in uremic patients. A high degree of binding to either albumin or α1-acid glycoprotein means little drug is available for removal by dialysis.|
|Amount of drug excreted in the urine unchanged||If ≥40% of a drug is excreted in the urine unchanged, it is highly likely to accumulate in patients with renal insufficiency.|
|Active metabolites excreted in the urine||The metabolites can accumulate, with attendant effects.|
|Volume of distribution||A small volume of distribution (that of total body water or less; that is, ≤0.7 liter/kg) means the drug may be accessible for dialytic removal if it is not highly protein bound. A large volume of distribution means little if any removal by dialysis.|
The amount of a drug or active metabolite excreted in the urine can allow predictions as to the potential for clinically important drug or metabolite accumulation in patients with renal insufficiency. In general, if about 40% or more of a drug dose is excreted in urine, dose adjustment will be needed in patients with renal insufficiency—assuming the drug in question has a sufficiently narrow therapeutic index to be of concern. An exception to this rule of thumb is drugs with the potential for undergoing a “futile cycle,” which refers to the fact that the metabolic route serves to form a reservoir for parent drug. Thus, the metabolic step is “futile” (see the section on metabolism). With such agents, little (if any) drug itself is normally excreted in the urine—yet renal insufficiency can result in its accumulation in plasma. The mechanism of this effect, and the few drugs to which it applies, are discussed in material following. It is also important to note that some drugs are metabolized to active metabolites in which case, both drug and metabolite are pharmacologically potent. Further, some drugs are pro-drugs, which are themselves inactive, but are converted to active compounds (e.g., clopidogrel or irnotecan). For these drugs, the focus of dosing adjustment should be on the active compounds.
It should be apparent from the foregoing that for drugs that have not been explicitly studied in patients with renal insufficiency one can make reasonable predictions as to the need for adjusting therapy. Although lack of quantitative guidelines makes dose adjustments tentative, a worse problem is ignoring the need to do so. When no information concerning the relevant characteristics of a drug is available, one therapeutic strategy is to use a drug of the same class—but with no dependence on the kidney for elimination. For example, if a clinician wishes to prescribe a cardio-selective beta-adrenergic antagonist to a patient with renal insufficiency one alternative is to administer atenolol in a modified dose. Another option is to administer metoprolol, which is eliminated by the liver and needs no dose adjustment in patients with renal insufficiency. The converse would apply to patients with liver disease. However, there is a growing body of literature that suggests that drug metabolism may be altered in patients with renal dysfunction, and increasingly the U.S. Food and Drug Administration is requiring studies of the effects of renal dysfunction on new drugs that are cleared by non-renal routes. Therefore, some caution should be exercised in simply switching a patient from a drug predominantly eliminated by the kidney to a drug with a predominant nonrenal elimination.
Role of the Kidney in Drug Disposition
Most drugs are excreted via the kidneys, either in the form of the unchanged drug molecule or after conversion of the parent drug into polar metabolites. Mechanisms by which the kidney excretes drugs are analogous to its normal physiologic processes of glomerular filtration, active secretion, and active and passive reabsorption. Below, the processes of importance for the handling of drugs are briefly described. Effects on any of these processes, e.g., through interactions between concomitantly administered drugs or through renal disease, can mandate changes in drug dosing. The influence of altered kidney function on systemic drug disposition, and corresponding dosing strategies are discussed in more detail in subsequent sections.
The glomerulus offers no barrier to filtration of the unbound fraction of most drugs. Glomerular pores allow passage of molecules up to molecular weights of about 65,000 Daltons, and the vast majority of xenobiotics (including many biologic agents) are approximately two orders of magnitude smaller than this. Exceptions include larger proteins and dextran. Dextran is a good example of the role of molecular size; it can be administered as several different preparations, the size of which determines their ability to be filtered. Thus, dextran 1 (MW=1000) is freely filtered and is eliminated rapidly by the kidney—with a half-life of elimination of about 2 hours. In contrast, dextran 70 is too large to be filtered and is eliminated slowly by metabolism. It is detectable in plasma for 4 to 6 weeks. Dextran 40 is a mixture of both higher- and lower-molecular-weight species so that the smaller dextrans are freely filtered and eliminated quickly, with selective retention of the larger components.
For drugs freely filtered at the glomerulus, such as aminoglycoside antibiotics, renal elimination can be quite rapid. For many other drugs, binding to serum proteins restricts filtration and thus only the unbound fraction can be filtered and renal excretion, depending on the extent of binding, may be negligible. The limits to glomerular filtration of a drug, then, are usually not the glomerular barrier itself but factors that prevent filtration—predominantly binding to macromolecules too large to be filtered.
Secretion and Reabsorption
The overall renal drug clearance is determined by the relative importance of filtration, secretion of drug into the primary urine, and reabsorption back into the blood. It follows that secretion must occur if the rate of excretion is higher than that of filtration, and conversely, if the rate of excretion is lower than the filtration rate, the drug is by necessity reabsorbed.
Secretion : The classical method described for assessing drug secretion by the kidney was that of Cross and Taggart, using incubations of renal cortical slices. The sine qua non for secretion was a slice-to-medium–concentration ratio greater than unity. Numerous more sophisticated methods for characterizing secretion have since evolved, including microperfusion of isolated nephron segments, use of isolated proximal tubular cells or vesicles derived from peritubular or luminal membranes of proximal tubules, and cellular expression systems for detailed studies of drug transport by specific membrane transporters.
Drugs gain access to secretory sites via the peritubular capillary. If 20% of renal plasma flow is filtered, the remaining 80% of flow reaches sites of secretion. This process is active because an uphill concentration gradient can be generated. Moreover, depriving the proximal tubule of energy also inhibits movement of drugs from the peritubular to the tubular side of the cell. The energy for active secretion is ultimately obtained from ATP hydrolysis, either directly driving transmembrane drug flux (i.e., primary active transport), or generating concentration gradients across the cell membranes that, in turn, drive the solute flux (secondary active transport). In the latter case, energy is generated by peritubular sodium-potassium exchange via Na + ,K + -ATPase.
The efficiency of secretion is quite impressive. For example, secretion occurs for many drugs that are highly protein bound (such as furosemide). For this and other drugs, the affinity for transport exceeds that for binding. As such, binding to plasma proteins actually facilitates elimination by increasing the amount of drug in the plasma and thereby delivering it to secretory sites. That this is the case has been demonstrated in studies with analbuminemic rats. Administration of furosemide to these animals results in very low plasma concentrations of diuretic because without albumin binding the drug distributes widely outside the vascular space. Consequently, only small amounts are delivered to secretory sites and little is excreted into the urine. Administration of albumin in this setting binds furosemide, keeping it in the vascular space so that more diuretic reaches secretory sites (where more can be secreted into the urine). A similar effect has been shown to occur in humans.
Reabsorption : The kidney is capable of both active and passive reabsorption of drugs. Various membrane transporters mediate active luminal-to-abluminal flux of substrate drugs, whereas passive drug reabsorption is the consequence of concentration differences between the primary urine and the blood in the peritubular capillaries, that in turn results either from active drug secretion or, typically, from the reabsorption of water along the nephron. Passive reabsorption relies on diffusion of drugs across the lipid bilayers of the renal tubule epithelium and favors nonpolar drugs. For passive diffusion of drugs that are weak acids or bases, the nonionized form of the drug will be passively reabsorbed since it can cross the tubular membranes. Hence, for both weak acids and bases, urine pH can influence passive reabsorption, and urine pH can be manipulated to reduce passive reabsorption and enhance renal elimination. For example, in the case of patients with aspirin overdose, sodium bicarbonate is administered to alkalinize the urine. In the alkaline urine, salicylate is present predominately in the ionized form and is therefore not reabsorbed.
Renal Drug Transporters
While energy-dependent solute transport in the kidney was demonstrated almost a century ago, the roles of transport proteins in the renal handling of drugs remain an active area of research. The human genome contains more than four hundred membrane transporters classified into the ATP-Binding Cassette (ABC) and Solute Carrier (SLC) gene families, in addition to the numerous aquaporins and ion channels that serve the same purpose of facilitating trans-membrane solute flux. Here, we limit the discussion to ABC and SLC membrane transporters that are known to transport drug molecules across the membranes of renal cells, either in the secretory or the reabsorptive direction ( Figure 95.1 ). Data on the clinical relevance of the various membrane transporters continues to emerge, and additional members are likely involved in the renal transport of some drugs. In this section we focus on the function and expression of renal drug transporters under physiological conditions, whereas the effects of renal disease is discussed in more detail below (See: Influence of Renal Disease on Drug Disposition and Response).
Early studies defined two separate transport systems for organic solutes in the kidneys, with broad substrate specificities towards organic anions and organic cations, respectively. During the past decades, a large number of distinct transport proteins have been identified as contributors to these transport systems, and functionally characterized with respect to their substrate specificities, cellular localization, genetic variation, and so on. The historical categorization based on substrate charge is, however, not directly mirrored in the assignment of transporters to different gene families based on similarity in amino acid sequence. While substrate specificities often are shared within subfamilies of structurally similar transporters, members of both the anion and the cation systems are found across multiple subfamilies in the ABC and SLC gene families, and some subfamilies contain both anion and cation transporting members.
ABC transporters : The human ABC gene family contains 49 distinct protein coding genes, divided into seven families (ABCA–ABCG) based on amino acid sequence similarity. All members contain a highly conserved ATP-binding region, and utilize energy from ATP hydrolysis to drive efflux of substrate molecules from the inside to the outside of cells. ABC transporters of importance for renal drug transport include P-glycoprotein (P-gp/ABCB1) and several members of the Multidrug Resistance Associated Protein (MRP/ABCC) subfamily. P-gp is by far the most well-characterized drug transporter, and has been shown to transport many structurally diverse compounds, typically of a lipophilic and uncharged or weakly basic character ( Table 95.2 ). P-gp is expressed in the luminal membrane of proximal tubule epithelium and appears to play a role in the renal clearance of digoxin.
|Transporter a||Gene Symbol||Selected Substrates|
|P-gp (MDR1)||ABCB1||Digoxin, doxorubicin, irinotecan, loperamide, paclitaxel, ritonavir, saquinavir, vinblastine|
|MRP1||ABCC1||Daunorubicin, doxorubicin, etoposide, leukotriene C4, methotrexate, saquinavir|
|MRP2 (cMOAT)||ABCC2||Methotrexate, statins, olmesartan, valsartan, glutathione and glucuronide conjugates|
|MRP3||ABCC3||Fexofenadine, methotrexate, glucuronide conjugates|
|MRP4||ABCC4||Adefovir, cyclic AMP, dehydroepiandrosterone sulphate, methotrexate, tenofovir, topotecan|
|MRP6||ABCC6||Leukotriene C4, BQ123|
|OCT2||SLC22A2||Amantadine, amiloride, cimetidine, cisplatin, histamin, metformin, serotonin|
|OCTN1||SLC22A4||Carnitine, pyrilamine, quinidine, verapamil|
|OCTN2||SLC22A5||Carnitine, cephaloridine, quinidine, verapamil|
|OAT1||SLC22A6||Acyclovir, adefovir, cidofovir, ciprofloxacin, lamivudine, methotrexate, tenofovir, zalcitabine, zidovudine|
|OAT2||SLC22A7||Allopurinol, bumetanide, dehydroepiandrosterone sulfate, estrone-3-sulfate, 5-fluorouracil|
|OAT3||SLC22A8||Bumetanide, cefaclor, ceftizoxime, furosemide, NSAIDs, estrone-3-sulfate|
|OAT4||SLC22A11||Bumetanide, NSAIDs, tetracycline, urate, zidovudine,|
|OATP4C1 (OATP-H)||SLCO4C1||Digoxin, estrone sulfate, methotrexate sitagliptin|
|PepT1||SLC15A1||Amoxicillin, captopril, cephalexin, cefadroxil, enalapril, glycylsarcosine, valacyclovir, dipeptides, tripeptides|
|PepT2||SLC15A2||Amoxicillin, captopril, cephalexin, cefadroxil, enalapril, glycylsarcosine, valacyclovir, dipeptides, tripeptides|
The MRP/ABCC family consists of thirteen transporters, many of which have been shown to accept drugs as substrates, in particular anionic drugs and compounds conjugated with sulfate, glucuronide and glutathione moieties ( Table 95.2 ). In the kidney proximal tubule epithelium, MRP2/ABCC2 and MRP4/ABCC4 are expressed in the luminal membrane and mediate secretion of substrates to the urine. MRP6/ABCC6 is also expressed in the kidney proximal tubules, but is instead localized to the basolateral membrane. Expression of MRP1/ABCC1 and MRP3/ABCC3 is highest in more distal parts of the nephron, including the thick ascending loop of Henle, distal tubuli and collecting duct, where their expression in the basolateral membrane suggests involvement in the reabsorption of organic anions. Based on in vivo studies in knockout mice, MRP4 appears to be important in the renal clearance of tenofovir and adefovir, two anti-viral drugs.
SLC transporters : More than 350 human membrane transporters are categorized to the SLC gene family. In contrast to the ABC family, transport by SLCs is not directly coupled to ATP hydrolysis, but is instead dependent on concentration gradients of the transported substrate or of co- or counter-transported ions or small endogenous molecules. The SLC family contains many of the transporters necessary for cellular nutrient uptake, including glucose transporters in the SLC2 and SLC5 subfamilies and amino acid transporters in the SLC1, SLC3, SLC6, SLC7, SLC36 and SLC38 subfamilies. Many of these are expressed along the nephron, where they have the important function of limiting the loss of essential nutrients to the urine. The di/tripeptide transporters PepT1/SLC15A1 and PepT2/SLC15A2 have a corresponding role in nutrient reabsorption, but also accept some peptidomimetic drugs as substrates, including β-lactam antibiotics like cephalexin and amoxicillin and angiotensin converting enzyme inhibitors like enalapril and fosinopril ( Table 95.2 ).
The SLC subfamilies with the most extensive evidence for a role in drug disposition are the organic anion (OAT) and organic cation (OCT) transporter family SLC22, the organic anion transporting polypeptide family OATP/SLCO, and the recently discovered multidrug and toxic compound extrusion family MATE/SLC47. The SLC22 family contains a mixture of structurally similar organic anion and organic cation transporters. In the kidney proximal tubule, OCT2/SLC22A2 is the primary transporter mediating cellular uptake of organic cations from the blood. Substrates are typically low molecular weight cations, and include drugs such as metformin, amiloride, procainamide, oxaliplatin and varenicline ( Table 95.2 ). Recently, MATE1/SLC47A1 and MATE2-K/SLC47A2 were identified as luminal exporters of organic cations in the proximal tubuli, and overlapping substrate and inhibitor specificities between the MATEs and OCT2 have led to the hypothesis that these form a complementary transport system for tubular secretion of small organic cations.
Renal organic anion transporters include OAT1–3/SLC22A6–8 and OAT4/SLC22A11. OAT1, 2 and 3 are expressed on the abluminal membrane of proximal tubule cells and mediate cellular uptake of anionic drugs such as para-aminohippuric acid, acyclovir, ciprofloxacin, methotrexate, ceftizoxime, and furosemide ( Table 95.2 ). OAT4 is expressed on the luminal membrane, and is involved in urate homeostasis and in the reabsorption and/or secretion of anionic drugs. In addition to the SLC22s, members of the OATP/SLCO family have been shown to transport numerous anionic drugs. In the kidney, the most prominent member is OATP4C1/SLCO4C1. In comparison to the hepatic OATPs 1B1, 1B3 and 2B1, OATP4C1 is so far much less studied. It mediates uptake from the blood into the proximal tubule cells, and substrate drugs include digoxin, estrone sulfate, methotrexate and sitagliptin.
Two other transporters in the SLC22 family have been implicated in renal drug elimination: OCTN1 (SLC22A4) and OCTN2 SLC22A5), which transports carnitine in the kidney. Mice with mutations in OCTN2 eliminate the model organic cation tetraethylammonium by renal excretion at about half the rate of their wild-type littermates.
Interindividual differences : Genetic variation in membrane transporters can result in increased or diminished drug transport. Such variation has been catalogued as part of genome-wide studies and in greater detail in gene family-focused efforts. Many commonly occurring genetic variants in important drug transporters have been characterized in cellular expression systems and some have also been shown to affect the in vivo disposition and pharmacological effect of substrate drugs. For example, torsemide renal clearance was correlated with genetic variation in OAT4/SLC22A11, and a common genetic variant (A270S) in OCT2/SLC22A2 was shown to result in changes in metformin clearance in multiple populations.
Several heritable diseases have genetic variants that result in non-functional transporters as their underlying cause. For example, Dubin-Johnson syndrome, which manifests as hyperbilirubinemia, is caused by mutations in MRP2/ABCC2 that reduces biliary excretion of bilirubin. The effects of Dubin-Johnson syndrome on renal drug handling is much less studied, but the pharmacokinetics of drugs that utilize MRP2/ABCC2 in their renal excretion may be affected in Dubin-Johnson patients.
In addition to genetic variants that cause direct functional effects by altering or truncating the amino acid sequence, mutations in regulatory genomic regions can have functional effects, by altering expression levels of the transporter. In fact, natural interindividual variation in transporter expression levels can be significant. In liver samples from 110 patients, MRP2/ABCC2 levels varied more than 300-fold, and expression level differences may thus have effects on drug disposition on par with or even greater than many coding region variants. Data on inter-individual differences in renal transporter expression is scarce, but such variation may ultimately affect the disposition of renally cleared drugs.
The kidney has the capacity to metabolize numerous drugs and proteins. The proximal nephron has high levels of glucuronyl transferases, sulfotransferases, and peptidases. The ability of the kidney to conjugate drugs via the transferases has been demonstrated unequivocally in animals, but data in man are fragmentary and less direct. Renal glucuronidation may be substantial. For example, approximately 20% of an intravenous dose of furosemide and 50% of a dose of morphine may be glucuronidated by the kidney.
When glucuronide is conjugated to a xenobiotic, the chemical bond between the two can be either an ether (e.g., phenolic) or an ester (e.g., carboxylic). The latter is called an “acyl-glucuronide.” Ether-linked glucuronides are chemically stable and are for the most part excreted in the urine. In contrast, acyl-glucuronides are unstable under physiologic conditions such that the glucuronide can deconjugate back to the parent compound. In addition, the glucuronic acid moiety can migrate to other parts of the molecule (acyl migration).
One implication of this chemical instability is analytical. Consider, for example, that one wishes to measure the amount of a drug excreted in the urine. If not just drug but its acyl-glucuronide is excreted, one must be certain that the metabolite does not deconjugate ex vivo —causing a falsely elevated measure of the parent drug. To avoid this phenomenon, samples of urine must be stabilized quickly in acidic buffer (e.g., using 75 µl of 17 M glacial acetic acid in a 20-ml urine aliquot is sufficient).
A second implication of acyl-glucuronide formation is the possibility of a futile cycle of drug metabolism ( Fig. 95.2 ). In patients with normal renal function, circulating acyl-glucuronide conjugates that are formed in the liver are readily eliminated in the urine. In patients with renal insufficiency, however, renal excretion is decreased and the conjugate accumulates in plasma—where it can spontaneously hydrolyze to reform the parent compound ( Fig. 95.2 ). This phenomenon leads to a paradox in which a drug may accumulate in patients with renal insufficiency even though negligible amounts of parent drug are eliminated in the urine in patients with normal renal function.
Clofibrate, diflunisal, and some of the arylpropionic NSAIDs have been shown to undergo a futile cycle. It would seem prudent to avoid drugs undergoing acyl-glucuronide conjugation in patients with renal insufficiency, or to at least use them very cautiously in such patients.
The proximal nephron also contains mixed-function cytochrome P450 oxidases (CYP), but in lower amounts than the liver. Interestingly, isoforms of CYP appear to be differentially regulated in the kidney relative to the liver. The relative contribution of renal compared to hepatic metabolism is unknown.
The kidney is able to metabolize proteins, such as insulin and other biologic agents—including interleukins, superoxide dismutase (SOD), and likely many others. In patients with normal renal function, up to 50% of insulin elimination occurs via renal metabolism. This component of overall elimination diminishes in patients with renal insufficiency and accounts at least in part for the decreased insulin requirement as a patient’s renal function deteriorates. Many biologic proteins, such as SOD, are small enough to be freely filtered by the glomerulus. They are then metabolized by the peptidases of the proximal tubule. When renal function declines, renal metabolism is decreased and the substance can accumulate.
Proximal tubule dipeptidases also metabolize imipenem. As such, if imipenem alone is administered to patients, all antibacterial effect in the urine is lost. To attain efficacy for urinary tract infections, imipenem is administered with cilastatin—which inhibits the dipeptidases, allowing sufficient amounts of unchanged imipenem in the urine to kill bacteria.
Overall, then, the kidney is metabolically active toward drugs in a variety of ways. Unfortunately, renal metabolic contributions to drug elimination in man have been inadequately explored and thus clinical implications are for the most part speculative.
In addition to the metabolic roles of the kidney described previously, the kidney excretes many drug metabolites formed in the liver. Renal insufficiency does not necessarily mean that drug metabolites will accumulate because other excretory pathways exist, such as biliary excretion. In addition, many drug metabolites presumably have no effects. On the other hand, there are numerous examples of metabolite accumulation in which the metabolites are pharmacologically active ( Table 95.3 ). Some of the metabolites listed exert pharmacologic effects similar to those of the parent compound (e.g., primidone). Others account for all of the pharmacologic activity, the parent compound having no effect (e.g., enalapril). In other examples, the metabolite has a different pharmacologic profile from the parent drug. For example, normeperidine excites the CNS and can cause seizures in contrast to the sedating effect of the parent compound meperidine.
|ANESTHETICS AND DRUGS USED DURING ANESTHESIA|
|Remifentanil||Carboxylic acid metabolite|
|ANTIANXIETY AGENTS, SEDATIVES, AND HYPNOTICS|
|ANTICOAGULANTS, ANTIFIBRINOLYTICS, AND ANTIPLATELET AGENTS|
|Valproic acid||Not identified|
|Oxaprozin||Two hydroxylated metabolites|
|Nalidixic acid||7-hydroxynalidixic acid|
|ANTINEOPLASTICS AND ANTIMETABOLITES|
|Chloracetaldehyde (oral dosing)|
|Dantrolene||Hydroxy and amino metabolites|
|Captopril||Mixed disulfides with endogenous thiols|
|BLOOD LIPID-LOWERING AGENTS|
|Clofibrate||Parachlorophenoxyisobutyric acid (CPIB)|
|Triamterene||Sulfuric ester of hydroxytriamterene|
It should be apparent that in order to safely use drugs with active metabolites in patients with renal insufficiency one must know the pharmacologic profile of the parent drug and its metabolite(s). One should try to avoid such drugs in patients with renal disease.
Influence of Drugs and Renal Disease on Drug Disposition and Response
Inter-individual variation in drug disposition among patients can lead to too high or too low systemic plasma levels and is a major factor in the safe and effective use of drugs. Variation may be associated with gender, age, concurrent drugs (drug-drug interactions) and disease. This section focuses on drug-drug interactions that occur in the kidney and on the effect of renal disease on drug disposition. The recent publication of a whitepaper co-authored by an International Transporter Consortium focused on the role of transporters in drug development and highlighted transporter based drug-drug interactions. Among the interactions described were drug interactions that occur in the kidney and that may contribute to drug toxicity. Clinicians should be aware of these interactions as they may interfere with rational drug therapy. With the molecular identity of many drug transporters, there is an emerging appreciation of the mechanisms that underlie renal drug-drug interactions. Similarly, with the advent of sensitive analytical methods and metabolomic studies, a new appreciation for the molecular mechanisms involved in renal disease induced changes in drug absorption and disposition has emerged. Further, advances in physiologic based pharmacokinetics have led to an increased understanding of the mechanisms by which renal disease may affect drug disposition. In this section, drug-drug interactions in the kidney are described first, followed by the effect of renal disease on drug disposition. New information is highlighted and where possible mechanistic explanations of how drug interactions or disease effects occur are included.
Influence of Drug-Drug Interactions on Renal Pharmacokinetics
Drug-drug interactions are important from a drug safety point of view. In fact, of the drugs withdrawn from the market because of drug safety issues, many are associated with clinical drug-drug interactions. Considerable information is available on drug-drug interactions that occur in the liver and for which one drug alters the metabolism of a second drug. In contrast, there are comparably few studies of drug-drug interactions in the kidney. The recent identification, characterization and localization of a number of ABC and SLC transporters in the kidney have led to increasing recognition of the potential importance of drug-drug interactions in the kidney. With the availability of recombinant human renal transporters expressed in continuous cell lines, it is now possible to determine the potential of various drugs to inhibit the renal transport of other drugs. The concentration of a drug that inhibits transport in cellular assays can be compared to its clinical concentrations to determine whether a potential drug-drug interaction is likely to occur in vivo . In vivo drug-drug interactions can be investigated in healthy populations or in patients to determine the magnitude of the interaction and whether dosing adjustments will be needed when drugs are administered concomitantly.
The magnitude of effect of a concomitant drug on the systemic blood levels of another drug depends on the following factors. First, the fraction of the dose of the affected drug that is eliminated in the kidney is an important factor. If the fraction is low, renal drug-drug interactions will be unimportant to the overall elimination of the drug. In contrast, for drugs for which a high fraction of the dose is eliminated in the kidney, renal drug-drug interactions may potentially be important. In particular, an interacting drug may inhibit the entire secretory component of renal elimination of the affected drug. If renal secretion constitutes, for example one-half of the renal clearance of the affected drug, then an interacting drug may reduce the renal clearance of the affected drug by one-half. Thus, to estimate the potential importance of a drug-drug interaction in the kidney, a comparison of the net secretory clearance to the total renal clearance of the drug should be made. Net secretory clearance is equal to total renal clearance minus filtration clearance, which in turn is equal to GFR x fraction unbound. So, for example, if a drug has a renal clearance of 50 ml/min and a fraction unbound of 0.01, then in a patient with a GFR of 100 ml/min, the net secretory clearance would be equal to 50 ml/min minus 0.01*100 ml/min or 49 ml/min. Thus a major portion of the renal clearance would be tubular secretion.
Drug-drug interactions in the kidney are often charge specific. That is, weakly acidic drugs will inhibit the renal elimination of other weakly acidic drugs and basic drugs will inhibit other weak bases. There are however a few drug-drug interactions that are not charge selective. Below clinical drug-drug interactions in the kidney are described for acidic drugs and basic drugs.
Clinical Drug-Drug Interactions Involving Acidic Drugs
As noted previously, many organic anions or weak acids are eliminated in the kidney by renal tubular secretion. In general, OAT1 and OAT3, localized to the basolateral membrane of proximal tubule cells, mediate the first step in the tubular secretion of organic anions. On the apical membrane, ABC transporters, including MRP2 and MRP4, transport acidic drugs into the tubule fluid for excretion. OAT4, on the luminal membrane, is thought to function primarily in reabsorption of anionic drugs, but may participate in secretion. In clinical studies, identification of the specific transporter involved in an interaction is often difficult given that most inhibitors can affect multiple transporters and are not selective for a single transporter. The major drug that has been shown to inhibit renal organic anion secretion is the uricosuric agent, probenecid. Clinical examples of drug-drug interactions with probenecid are shown in Table 95.4 and include a number of cephalosporins and anti-viral agents. In general these drug-drug interactions result in higher systemic blood levels and may cause potential toxicities of the affected drug. Probenecid itself is not substantially eliminated in the kidney; therefore its renal disposition is not altered during the drug-drug interaction. Probenecid has long been used to extend therapeutic plasma levels of penicillins by reducing its renal clearance. It is notable that probenecid has been shown to protect the kidney from the nephrotoxic anti-viral drug, cidofovir. In fact, the approved cidofovir label contains the following warning:
“Renal impairment is the major toxicity of Vistide (cidofovir). Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of Vistide. To reduce possible nephrotoxicity, intravenous prehydration with normal saline and administration of probenecid must be used with each Vistide infusion.”
|Organic Anion Transport Mediated Drug–Drug Interactions|
|ORGANIC CATION TRANSPORT MEDIATED DRUG-DRUG INTERACTIONS|
While not completely understood, evidence suggests that the mechanism of the cidofovir renal toxicity is related to high drug concentrations in proximal tubule cells. Co-administration with probenecid leads to a redirection of cidofovir elimination to almost exclusively involve glomerular filtration, a markedly decreased cellular accumulation, and the prevention of clinical signs of nephrotoxicity. Thus, probenecid exemplifies that drug-drug interactions in the kidney can have pronounced effects on drug levels, and that inhibitors of renal drug transport can be exploited in drug therapy.
Clinical Drug-Drug Interactions Involving Cationic Drugs
Many hydrophilic organic cations are eliminated by renal secretion. Notable examples include the anti- diabetic drug metformin and the anti-viral drug, zidovudine. Other examples are listed in Table 95.4 . OCT2 is thought to mediate the first step in tubular secretion of organic cations across the basolateral membrane. On the apical membrane, two transporters are thought to be involved: MATE1 and MATE2-K. Whereas OCT2 is a facilitative transporter that mediates drug transport in accordance with the electrochemical gradient, MATE1 and MATE2-K appear to be proton exchangers. That is, these transporters efflux their cationic substrates in an apparent electroneutral exchange with protons. Although other inhibitors of tubular secretion of organic cations have been described, cimetidine is the major perpetrator of renal drug-drug interactions that involve organic cations. Until recently, it was thought that the cimetidine mediated renal drug-drug interaction occurred at OCT2; however, recent studies have shown that cimetidine is actually a more potent inhibitor of MATE1. Thus, in vivo, cimetidine may inhibit renal transport of organic cations at MATE1 and not at OCT2.
Digoxin is a neutral compound, which is eliminated primarily in the kidney with a small component of tubular secretion. P-glycoprotein (ABCB1) appears to mediate its renal secretion and a number of P-glycoprotein inhibitors including verapamil, ritonavir, itraconazole and quinidine have been found to inhibit its tubular secretion.
Influence of Renal Disease on Drug Disposition and Response
As illustrated in Fig. 95.3 , the concentration of a drug in plasma is influenced by a number of factors—each of which, including processes that are not directly associated with the kidneys, may be affected by renal disease. This can lead to altered drug disposition and ultimately to toxic accumulation of drugs or the loss of pharmacological effect. The dose and dosing interval of a drug are controlled by the physician, and altering them is the only method of compensating for alterations in drug disposition in the patient.
By several theoretical mechanisms, renal disease could affect drug absorption. Altered intestinal motility could change rates of gastric emptying of medications to small intestinal absorption sites. Changed regional distribution of blood flow could affect absorption from intramuscular or subcutaneous sites. Such effects on drug absorption remain speculative. Based on current data, clinicians may assume that drug absorption is not changed in patients with renal insufficiency.
Although not strictly an absorptive process, first-pass metabolism by the intestinal mucosa and liver influences the systemic availability of a drug after oral dosing. By largely uncharacterized mechanisms, renal insufficiency can also diminish non-renal (presumably hepatic) elimination of some drugs. For drugs with substantial first-pass elimination, such inhibition of hepatic metabolism could cause greater bioavailability. This mechanism may account for the apparent increase in propoxyphene bioavailability in patients with severe renal insufficiency. Because this phenomenon has not been described with other drugs, clinicians should not extrapolate these findings to all drugs that undergo first-pass elimination.
Systemic pH can affect distribution of drugs into tissues. A pH favoring the non-ionized form of a weak acid or base can facilitate its distribution out of plasma and into tissues. This phenomenon has been demonstrated to occur with salicylate. Being a weak acid, a more acidic systemic pH increases the relative amount of non-ionized salicylate and increases the amount reaching the central nervous system (CNS) and toxicity. Presumably the acidemia of uremia would increase access of salicylate into the CNS. A similar phenomenon has not been described with other drugs, although this area is little studied.
Protein binding of highly bound drugs is another major determinant of drug distribution. Many acidic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide and loop diuretics, penicillins, and others bind predominantly to albumin—whereas basic compounds such as lidocaine, propranolol, tricyclic antidepressants, and so on typically bind to the acute-phase reactant α1-acid glycoprotein. Patients with renal insufficiency accumulate endogenous organic acids that are normally excreted by the kidney, and these compounds are able to displace acidic drugs from albumin binding sites. The likelihood that such an effect will be important is a function of the degree of binding of the drug. Generally, for drugs bound less than 90% the magnitude of effect is so small as to be irrelevant. In contrast, drugs bound more than 90% may be importantly affected by changes in binding. For example, NSAIDs are more than 99% bound to albumin. Thus, less than 1% is free in plasma and constitutes the active moiety. In uremia, what may appear to be a trivial decrease in binding from 99 to 98% actually results in a doubling of the free unbound concentration from 1 to 2%—a magnitude of change that may be clinically important. In contrast, only about 50% of methotrexate is bound to albumin. A decrease in binding to 45% would have only a minor, clinically negligible effect on unbound methotrexate concentrations.
A frequent misconception is that such an effect results in increased concentrations of unbound pharmacologically active drug, causing an enhanced effect—including toxicity. In the majority of instances, however, there is no increase in concentration of unbound drug and therefore no change in response unless caused by other factors. The reason unbound drug concentrations are unchanged is that for many drugs with low total clearance (obeying so-called “restrictive” elimination, in which unbound clearance equals intrinsic clearance), clearance of total drug from plasma from all routes of elimination is directly related to the fraction of unbound drug, calculated as:
CL total = fu × CLu
where CL is clearance, fu is fraction unbound, and CLu is unbound clearance. Thus, if displacement from albumin causes the unbound fraction to increase, total clearance increases proportionally but unbound or intrinsic clearance is unchanged—resulting in maintenance of the unbound concentration and pharmacologic effect at its previous level. This similar unbound concentration occurs at a lower total drug concentration. Thus, the fraction that is unbound is increased but the concentration unbound is unchanged.
This scenario is true for acidic drugs that are highly protein bound and have low total clearances when displaced from albumin binding sites in uremia. Some other drugs have high organ clearances and extraction rates such that their clearance is less dependent on protein binding but partially or totally dependent on organ blood flow. In this case, unbound clearance will decline as the fraction unbound increases so that unbound drug concentrations increase despite, in some cases, an unchanged total drug concentration. Here, the opposite problem exists in that a dosage adjustment may be necessary even though total drug concentration changes little (if at all).
The degree of protein binding can also allow one to predict the potential for dialytic removal of a drug. A high degree of binding means only small amounts of drug are free in plasma and can be removed by the dialysis procedure. Drugs, either acidic or basic, that are more than 90% bound to plasma proteins will have negligible removal by dialytic procedures except hemoperfusion techniques.
The binding changes described previously can influence the calculation of distribution volume. If calculated based on total drug concentration, the volume of distribution may become larger when binding decreases—particularly for drugs that distribute extensively into intracellular sites and therefore have large volumes of distribution. This observation alone can lead to the false conclusion that loading doses need to be increased. In contrast, the distribution volume of the unbound pharmacologically active drug is essentially unchanged—meaning that no adjustment of loading dose should be made. For drugs with smaller volumes of distribution, particularly those restricted to extracellular sites, the total volume of distribution may be insensitive to changes in protein binding. However, there would be almost proportional changes in the unbound volume of distribution, and consequently loading doses should be adjusted.
Unfortunately, the medical literature concerning changes in drug disposition in patients with renal insufficiency is replete with data ignoring unbound drug concentrations. For highly bound drugs, if disposition parameters for total drug (clearance and volume of distribution) are the only values reported—and if these values are increased in patients with renal insufficiency—one must be suspicious that the effect is solely due to displacement from binding. The implication of this conclusion is that disposition parameters for unbound drug are unchanged and that no alteration in dosing is indicated. Clinicians and scientists should be alert to the potential for misinformation from a good deal of the medical literature concerning drugs subject to this phenomenon.
Reductions in protein binding in uremic patients, or with the hypoalbuminemia of nephrotic syndrome, can lead to misinterpretation of serum concentrations of phenytoin owing to the mechanisms discussed previously. In both clinical conditions, binding of phenytoin is decreased. Unbound concentrations are unchanged, although total concentrations are diminished. If plasma concentrations of phenytoin are obtained in a patient, the clinical laboratory reports total concentration—a value that could be misinterpreted as being too low even though unbound concentrations are within the therapeutic range. If the misled clinician increased the dose of phenytoin in an attempt to attain a total concentration in the usual therapeutic range, so doing would also increase the unbound concentration of phenytoin and could result in toxicity. This problem can be avoided by measuring unbound concentrations. Alternatively, one can redefine the therapeutic range for uremic and hypoalbuminemic patients.
Displacement from protein binding in patients with renal insufficiency has therefore been a misunderstood and misinterpreted phenomenon. This mechanism is too often cited as causal of altered response to drugs in patients with renal disease. However, because unbound drug concentrations often do not change this mechanism cannot explain altered response to drugs in many uremic patients. Moreover, displacement from binding does not necessarily mandate a change in drug dosing. Clinicians should avoid false conclusions regarding drug disposition from what may be incomplete data in the medical literature; namely, studies of highly bound drugs that quantify only total and not unbound concentrations. The clinical setting in which this phenomenon is most apparent is use of phenytoin in uremic or hypoalbuminemic patients, as described previously.
Digoxin represents a drug for which volume of distribution decreases as renal function diminishes:
Volume of distribution ( liters / kg ) = 3.84 + 0.0446 CLcr ( ml / min ) .
The mechanism of this effect is unknown, but the magnitude is sufficient to mandate dose adjustment. Because volume of distribution influences the loading dose of a drug (as opposed to the maintenance dose), this effect is important only in patients to whom a loading dose is administered. From the previous equation, it should be apparent that the loading dose of digoxin for a patient with end-stage renal disease should be approximately half that of a patient with normal renal function.
Both glomerular filtration and active secretion are typically reduced in patients with renal insufficiency, with possible implication for dosing strategies. Renal failure is accompanied by elevated levels of metabolic products that would normally be renally excreted, and that have been associated with multiple pathologies in uremic patients including neuropathy, hypertension, cardiac failure and increased bleeding. The molecular identities of these uremic toxins are largely unknown, but elevated levels of, e.g., hippuric acid, indoxyl sulfate, guanidino succinate, trans-aconitate, and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) have been demonstrated in plasma from uremic patients, and have been demonstrated to cause some of the pathological processes in model systems of renal failure.
It has long been appreciated that constituents of uremic serum can affect renal transport processes. Serum from uremic patients inhibited the uptake of the model organic anion para-aminohippuric acid (PAH) in kidney slices and isolated renal tubules from rat and rabbit, and, more recently, CMPF was shown to affect renal PAH uptake, likely through competitive inhibition of the OAT1 and OAT3 transporters Similarly, indoxyl sulfate is accumulated in the proximal tubuli of uremic rats, as well as in OAT1/3-expressing human proximal tubuli cells, and may thus compete with tubular uptake of substrate drugs.
In addition to direct inhibition by uremic toxins, several studies demonstrate altered expression of membrane transporters in models of renal disease. For example, decreased expression of OCT2, OAT1, OAT3 and MATE1 have been observed in rats with chronic renal failure. In contrast, renal expression of the efflux transporters P-gp and MRP2 were increased in such rats, possibly as a mechanism of protection from toxic accumulation in proximal tubuli cells.
Notably, the effects of accumulated uremic toxins are not limited to transporters in the kidney. An increasing body of literature demonstrates effects of renal disease on transporter function and expression also in other organs, including the intestine and liver. Inhibition of hepatic drug-metabolizing enzymes has also been demonstrated, including the Cytochrome P450s CYP2C9, CYP2C19 and CYP3A4. These extra-renal effects have important implications for drug therapy in renal disease, since dosing changes may be necessary also for drugs that undergo extensive hepatic metabolism or are cleared through biliary excretion. In line with the evidence for extra-renal pharmacokinetic effects of renal disease, the U. S. Food and Drug Administration (FDA) now recommends performing pharmacokinetic studies in patients with varying stages of renal impairment, for all chronically administered drugs, regardless of clearance pathway.
Even if the plasma concentration of a drug in a patient with renal insufficiency is identical to that of a patient with normal renal function, response may differ. For example, the effect of pindolol to block exercise-induced increases in heart rate and its effects to decrease plasma renin activity were greater in uremic patients than in normal volunteers despite similar serum concentrations of this beta-adrenergic antagonist. As such, an approximate fourfold greater plasma concentration was required in healthy subjects to cause the same effect on heart rate as in uremic patients. The mechanism of this enhanced response is unknown.
Unfortunately, comparable studies are not available with the host of drugs used commonly in patients with renal insufficiency. Clinicians must therefore use caution when using drugs in patients with renal disease in addition to adjusting doses to compensate for changes in disposition.
Just as dialytic procedures are used to remove accumulated endogenous end products of metabolism, they can remove drugs and their metabolites. With some drugs, the amount removed is sufficient to require supplemental dosing—or in poisoning settings is helpful in speeding the elimination of the toxin(s).
Drugs restricted to the extracellular, and particularly the plasma, compartment are accessible to removal by hemodialysis unless precluded by protein binding. Drugs with small volumes of distribution on the order of total body water or less (i.e., about 0.7 liter/kg) are likely but not necessarily restricted to the extracellular space, whereas a large volume of distribution often implies wide disbursement of drug throughout tissues. A drug with a small volume of distribution and low-protein binding (e.g., aminoglycoside antibiotics) would be predicted to be substantially removed by dialytic procedures and likely require supplemental dosing after dialysis. In contrast, a drug with a large volume of distribution may pass through a dialysis membrane. However, so little of the drug is in the plasma relative to overall body stores that the amount removed is negligible.
The best method of calculating drug clearance by peritoneal or hemodialysis is to actually measure how much drug is removed. So doing serves as an integrated function of dialyzer clearance throughout the entire procedure. The calculation is as follows:
Dialyzer clearance = Total amount of drug recovered in the dialysate / Duration of dialysis × drug concentration at the midpoint of dialysis .