British Journal of Anaesthesia 1993; 71: 282-290

REVIEW ARTICLE

EFFECT OF RENAL FAILURE ON DRUG METABOLISM BY THE LIVER A. C. ELSTON, M. K. BAYLISS AND G. R. PARK The selection of a safe and effective drug regimen for patients with renal impairment can be difficult. Data obtained from studies in people with normal renal function cannot be used to design drug therapy for patients with renal failure. Many drugs and their metabolites undergo renal excretion and therefore accumulate in renal failure. However, relatively little is known about the effect of renal impairment on drug metabolism by the liver. Drug metabolism is a process that alters the pharmacological activity and rate of excretion of a drug. It consists of reactions such as oxidation and reduction in which a new functional group is created, and conjugation reactions in which substances such as glucuronic acid, sulphate or amino acids are added to the molecule. The product of metabolism is generally inactive and water soluble, and can be excreted in either the urine or the bile. Renal failure may influence hepatic drug metabolism either by inducing or inhibiting hepatic enzymes, or by its effects on other variables such as protein binding, hepatic blood flow and accumulation of metabolites. This review examines all of these effects. In order to investigate the effect of renal impairment on hepatic drug metabolism in vivo, it is necessary to study the effect of renal disease on systemic metabolic clearance. A brief outline of clearance and other pharmacokinetic variables examined in this review is given below. PHARMACOKINETIC CONCEPTS

Clearance Clearance is the term used to describe the intrinsic ability of the body to clear a drug from the blood or plasma. Total clearance is defined as die volume of plasma which can be cleared of a drug by the metabolizing organ, or the kidney, in unit time. Clearance is additive and total clearance includes renal, metabolic and biliary clearances: where CL? = total clearance; C/H = renal clearance; C/M = metabolic clearance; ClB = biliary clearance. Metabolic clearance can usually be taken to represent hepatic metabolism, although a few drugs such as

midazolam [73], morphine [17] and propofol [31, 39] undergo substantial extrahepatic metabolism. Biliary clearance is usually small so, for most drugs, if total and renal clearances are known, metabolic clearance can be calculated from the difference. However, there are some drugs such as acebutolol [51] that undergo active biliary secretion and have significant biliary clearances which must be measured. Total clearance is inversely proportional to the area under the plasma concentration vs time curve (AUC). As AUC depends also on the dose of drug administered, total clearance may be defined by the following equation: Dose AUC Systemic metabolic clearance depends on hepatic blood flow, the plasma concentration of unbound drug and intrinsic hepatic clearance. Intrinsic hepatic clearance is the theoretical maximum clearance of unbound drug by the liver in the presence of unrestricted hepatic blood flow [50] and is therefore a measure of the metabolic capacity of liver enzymes. Intrinsic clearance can be changed only by alterations in the metabolizing enzymes (induction or inhibition), so any differences in intrinsic clearance observed in patients with renal failure compared with healthy controls signifies a change in enzyme function. Metabolic clearance can be defined also by the equation: 1

ClM = Qn x E

where QH = hepatic bloodflow;£ = extraction ratio. The extraction ratio is the fraction of drug removed from the blood during its passage through the liver, and is defined by the following equation: E= where Ca = arterial concentration of drug; Cv = venous concentration of the drug. Drugs with a large metabolic clearance (> 1000 ml min"1), such as proANNE C. ELSTON, M.B., B.S., F.F.A.R.C.S.I.; GILBERT R. PARK*,

M.D., F.R.C.A. ; Addenbrooke's Hospital, Hills Road, Cambridge,

(Br. J. Anaesth. 1993; 71: 282-290) KEY WORDS Kidney: failure. Pharmacokinetics. Metabolism.

CB2 2QQ. MARTIN K. BAYLISS, B.SC., PH.D., Glaxo Group

Research, Park Road, Ware, Hertfordshire, SGI2 0DP. Accepted for Publication: February 15, 1993. •Address for correspondence: The John Farman Intensive Care Unit, Box 17, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ.

RENAL FAILURE AND HEPATIC DRUG METABOLISM pranolol and verapamil, have extraction ratios greater than 0.7 and elimination is perfusion-dependent. Drugs with a small metabolic clearance (< 300 ml min"1), such as diazepam and theophylline, have extraction ratios less than 0.2 and elimination is perfusion-independent. The clearance of most drugs with a small extraction ratio depends on the extent of protein binding and intrinsic clearance [83]. Distribution

Drugs are distributed from the plasma to the tissues and to proteins in the plasma and in the tissues. The extent to which a drug is distributed to the tissues is measured by the volume of distribution (F). This is not a real volume—it refers to the apparent volume of plasma which the dose of a drug would have to occupy in order to obtain the observed plasma concentration. Thus it merely relates the plasma concentration of a drug to the amount of drug in the body at a given time, it may exceed the plasma volume (5 litre) or even the total body water volume (60 litre). The extent to which drugs bind to plasma proteins varies from 0 % (lithium) to 99 % (warfarin). Acidic and neutral drugs tend to bind to albumin, while basic drugs bind more commonly to otj-acid glycoprotein. Free and protein-bound drug both undergo distribution, although protein binding restricts distribution considerably, as only unbound drug can enter cells. An equilibrium exists between bound and unbound drug, and as the unbound fraction is removed from the plasma by elimination, distribution, or both, bound drug dissociates from its binding sites. About 60 % of total body albumin is extravascular, so tissue protein binding also plays an important part in drug distribution.

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TABLE I. Changes in binding of drugs to plasma proteins in patients with renal failure

Change in binding

Drug Acidic drugs Dcsmethyldiazepam Phenytoin Benzyl penicillin Salicylate Fruscmide Warfarin Basic drugs Disopyramide Vancomycin Thiopentone Morphine

Decreased Decreased Decreased Decreased Decreased Decreased

[63] [3, 44, 65, 67, 72] [33] [3, 33, 57] [4, 68] [7, 13]

Increased [43] Decreased [75] Decreased [3, 40] Decreased [67]

Thus the elimination half-life of a drug is governed by its volume of distribution and clearance:

7j = 0.693 xiJJ Bio availability When a drug is given orally, the whole dose may not reach the systemic circulation. This is because the drug may be absorbed incompletely from the gastrointestinal tract, or it may undergo presystemic elimination, either in the liver or, less commonly, in the gut mucosa (first pass effect). Bioavailability (F) is the term used to describe the fraction of an oral dose that reaches the systemic circulation. It is usually obtained from the ratio of the AUC after oral and that after i.v. administration of a drug. FACTORS AFFECTING DRUG METABOLISM IN RENAL FAILURE

Protein binding

Half-life Plasma elimination half-life is the term most commonly used to express the duration of action of a drug; it is defined as the time taken for the plasma concentration of drug to decrease by 50 %, after the distribution equilibrium has been attained. As the elimination of most drugs takes place according to first-order rate kinetics, the rate of decrease of plasma concentration depends on the concentration of drug present in the plasma at time t and the elimination rate constant (k): dt The elimination half-life (T±) is a reflection of the elimination rate constant and is denned by the equation:

The duration of action of a drug depends also on the volume of distribution, as it is the extent of distribution which determines the actual concentration of drug in the plasma that is presented to the clearing organ. Clearance also affects the duration of action of a drug, as it measures the intrinsic ability of the body to eliminate the drug.

In uraemic patients, the binding of many acidic drugs to albumin is reduced [71] (table I). For drugs that are highly protein-bound and have a small extraction ratio, this may lead to an increase in hepatic clearance [3]. The mechanism for the change in protein binding in renal failure is unknown. As the plasma concentration of albumin correlates poorly with the decrease in protein binding, it has been suggested that a conformational change in the albumin molecule in renal failure may reduce its drug binding capacity [49]. Alternatively, accumulation of substances such as drug metabolites, free fatty acids or organic acids may occur, and these may compete with drugs for binding sites on the albumin molecule [32]. No correlation has been found between the decrease in protein binding and the severity of renal impairment as reflected by conventional biochemical markers of renal function such as serum creatinine [44, 67]. Alterations in protein binding in renal failure are not corrected by haemofiltration [70]. Basic drugs bind mainly to a,-acid glycoprotein (AAG) and the effect of renal insufficiency on their binding is controversial (table I). Despite the fact that increased plasma concentrations of AAG are found commonly in patients with chronic renal failure [43], the protein binding of basic drugs is largely unaffected by renal insufficiency [71]. How-

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Renal failure may affect isoenzymes differently, which may explain why the effect of renal disease on drug metabolism varies for different drugs. It has been suggested that, in renal failure, a substance(s) that induces certain cytochrome P-450 isoenzymes builds up in the plasma. Initially, it was thought that an enzyme inducer might be leached out of dialysis tubing [38]. However, this was not supported by the finding that accelerated antipyrine metabolism occurred in all patients with chronic renal failure, irrespective of whether they had received haemodialysis [58]. Another theory is that the enzyme inducer present in uraemic plasma is a dietary substance, or a metabolite of a dietary substance, that accumulates in renal failure [69]. For example, cruciferous plants contain naturally occurring indoles, that are potent inducers of microsomal hydroxylation in the rat [55]. Two studies [54, 64] have shown that, after phenytoin is given i.v., the elimination half-life is significantly shorter in patients with renal failure than in patients with normal renal function. This could not be explained by a change in volume of distribution, as decreased protein binding resulted in an increase in volume of distribution in both studies. It was suggested, therefore, that the decrease in elimination half-life was caused by induction of phenytoin metabolism, leading to an increase in metabolic clearance. Fosinopril is a new angiotensin-converting enzyme inhibitor that undergoes dual elimination through the liver and the kidney. It has been shown that, as renal function declines, there is a compensatory increase in the hepatic clearance of fosinopril when it is given i.v. [45]. Thus, although renal clearance decreases, total clearance remains unchanged. Accelerated metabolism and increased biliary excretion were shown to account for the increased hepatic clearance in this study. Similarly, although the renal clearance of i.v. cefpiramide has been shown to decrease linearly with creatinine clearance, total clearance remained unchanged because of a compensatory increase in metabolic clearance [28]. Nifedipine, which is eliminated almost entirely by metabolism, has a significantly greater total clearance in patients with terminal renal failure after oral and i.v. administration [19]. No differences in protein binding were found between healthy volunteers and patients with renal failure, and the increased total clearance may represent an increase in metabolism. However, all the patients in this study were receiving long-term haemodialysis and it has been suggested that this may increase splanchnic blood flow [9]. As nifedipine has a large extraction ratio, an increase in hepatic blood flow could account for the increased hepatic clearance seen in this study. Another drug oxidized by the liver that has accelerated metabolism in patients with renal failure is antipyrine. It has been shown that the plasma halflife of antipyrine given i.v. is decreased in patients with chronic renal failure [58]. As there was no significant difference between the volume of distribution in patients with chronic renal failure and normal subjects, the decrease in plasma half-life is

BRITISH JOURNAL OF ANAESTHESIA likely to reflect an increase in antipyrine oxidation, resulting in an increase in metabolic clearance. A possible mechanism suggested for this is enzyme induction by endogenous or dietary substances that accumulate in renal failure. Accumulation of substances found in the water supply, such as insecticides, may also cause enzyme induction [27]. This could be especially important in patients receiving haemodialysis, who are exposed to large volumes of water. Conflicting results have shown that, when antipyrine is given orally to patients with renal failure, demethylation of antipyrine is decreased, while hydroxylation is unchanged [77]. This shows that renal failure affects not only individual drugs differently, but also each metabolic pathway by which they are eliminated. Conjugation reactions have been studied in rats that have undergone bilateral nephrectomy [22]. This work showed that glucuronyl transferase activity is increased in acute uraemia, and suggests that the mechanism may be induction by phenols that accumulate in renal failure. Phenols and other uraemic toxins are inactivated by glucuronidation, so this may be an important homeostatic mechanism. Increased hepatic acetylation of sulphadimidine, another conjugation reaction, occurs in patients with chronic uraemia [35], although this effect is reversed by long-term haemodialysis. The mechanism for this may be induction of hepatic acetylation by amines that accumulate in uraemia and are removed by haemodialysis. Acetylation is an important detoxification pathway for many amines, so the increase in acetylation in patients with renal failure may be a compensatory response. Inhibition. In contrast to the above findings, the metabolic clearances of other drugs appear to be decreased in patients with impaired renal function (table II); this may result from inhibition of hepatic drug metabolizing enzymes. Inhibition of cytochrome P-450 isoenzymes may be caused by inhibition of enzyme synthesis, increased destruction of pre-existing enzymes, formation of drug-enzyme complexes that inactivate the enzyme, or depletion of cofactors. Alternatively, substances may accumulate in renal failure that are competitive inhibitors of drug-metabolizing enzymes. It is not yet known which of these mechanisms is responsible for the inhibition of drug metabolism in renal failure. It has been suggested that a circulating enzyme inhibitor is present in uraemic plasma in the rat [76]. In that study, livers from healthy rats and rats with uranyl nitrate-induced renal failure, were perfused with either uraemic or non-uraemic blood. In both groups of liver perfused with uraemic blood, the hepatic extraction of propranolol was significantly decreased. The exact nature of the proposed circulating enzyme inhibitor is unknown, although many endogenous substances, such as amines, organic acids, indolic derivatives, amino acids and peptides, accumulate in renal failure and could be responsible for the enzyme inhibition [14, 76]. Another study in rats [52], has shown that the decreased hepatic drug metabolism seen in renal failure may be caused by a deficiency of 5-aminolaevulinic acid, which is necessary for cyto-

RENAL FAILURE AND HEPATIC DRUG METABOLISM chrome P-450 enzymes synthesis. In this study, the decreased cytochrome P-450 content and activity seen in liver microsomes from uraemic rats, could be corrected by treatment of the rats with 8-aminolaevulinic acid. Two studies have shown that the non-renal clearance of metoclopramide, given i.v., is decreased in patients with renal impairment [11, 53]. The authors suggested that this could be caused by an alteration in entero-hepatic circulation or a decrease in renal metabolism; however, inhibition of hepatic metabolizing enzymes by uraemic plasma could not be excluded. The plasma clearance of nicardipine, given i.v., is significantly reduced in patients with renal impairment, but restored towards normal in patients with end-stage renal failure undergoing haemodialysis [1]. Less than 1 % of a dose of nicardipine is excreted unchanged in the urine, so the decrease in plasma clearance reflects a decrease in metabolic clearance. No significant differences in the measured indices of hepatic function were found to explain the decrease in metabolic clearance in the patients with renal impairment, and accumulation of a dialysable inhibitor of metabolism was suggested as a possible mechanism. Unfortunately, plasma concentrations of nicardipine metabolites were not measured in this study, so product inhibition by accumulation of metabolites cannot be excluded as a cause for the decrease in hepatic clearance. Studies with nitrendipine, another calcium channel blocker, have shown conflicting results in patients with renal failure. One study [5] found that after 7 days of oral treatment with nitrendipine, the total clearance was less in patients with renal failure than in control patients. As nitrendipine is eliminated almost entirely by hepatic metabolism, it was suggested that the decrease in total clearance reflected a reduction in hepatic extraction. However, intestinal absorption was not measured in this study, so the results must be interpreted with caution. Two similar studies [6, 20] failed to show any changes in the pharmacokinetic parameters of nitrendipine given orally or i.v. to patients with renal failure. The pharmacokinetics of a single bolus dose of verapamil given orally or i.v. were studied in normal volunteers and patients with advanced renal failure [74]. The mean non-renal clearance was decreased in patients with renal failure whether the drug was given i.v. or orally. However, two other studies [62, 85] did not show any significant changes in the pharmacokinetics of verapamil when it was given orally or i.v. to patients with diminished renal function. Patients in these two studies were receiving regular haemodialysis, whereas it was not stated if this was the case in the first study. Such a difference could explain the discrepancy in the findings. The AUC of nimodipine given orally increased in patients with impaired renal function [48]. In this study, intestinal absorption was not affected by renal failure, so the increase in AUC may represent a decrease in clearance, which for nimodipine comprises mainly metabolic clearance. However, the patients with renal insufficiency were significantly older than the volunteers, and the difference in age

287

rather than renal function may have been responsible for the pharmacokinetic changes. Furthermore, a control group was not included in this study; instead, the findings in patients with renal impairment were compared with pre-existing data on the pharmacokinetics of nimodipine in volunteers. When erythromycin was given orally, the maximum serum concentrations and AUC were found to be greater in patients with renal failure than in healthy control subjects [47]. There was no difference in elimination half-life between the two groups. As the volume of distribution of erythromycin is known to increase in renal failure, the increased plasma concentrations were thought to represent an increase in bioavailability. This could have been caused by either an increase in the extent of intestinal absorption, or a decrease in first pass effect. The former is unlikely, as the time taken to reach the maximum plasma concentration (rCmax) was the same in both groups. Thus decreased first pass metabolism would seem to be the most likely explanation for the pharmacokinetic changes. This may have been caused by a decrease in hepatic metabolism; however, erythromycin is also metabolized in the gut wall, so a decrease in intestinal metabolism cannot be excluded. The increased bioavailability shown in this study is important clinically, as increased plasma concentrations of erythromycin are associated with ototoxicity. The dose of erythromycin should therefore be decreased in uraemic patients. The bioavailability of oral propranolol, a drug which undergoes significant first pass metabolism, is greater in patients with chronic renal failure not receiving haemodialysis than in patients receiving haemodialysis or in healthy volunteers [15]. No differences in volume of distribution, elimination half-life, protein binding or absorption were seen between the patient groups, so the increase in bioavailability may be assumed to reflect a decrease in hepatic clearance. Propranolol was not extracted by dialysis, but the difference in bioavailability between the dialysed and non-dialysed groups may be explained by the presence of a dialysable factor in uraemic plasma that inhibits hepatic metabolism. However, another study has shown that the bioavailability of oral propranolol is increased in uraemic patients receiving regular haemodialysis [56]. This study showed that the intestinal absorption of propranolol was not altered by renal insufficiency, and concluded that the increase in bioavailability was caused by a decrease in hepatic metabolism. In another study [78] on the pharmacokinetics of uC-labelled propranolol, given both orally and i.v., no delay in the conversion of propranolol to its 4-hydroxy or conjugate metabolites was seen in patients with renal failure (not receiving haemodialysis) compared with control subjects. The creatinine clearances of the patients in this study were greater (2-62 ml min"1) than those in the two previous studies (0-10 ml min~l), and this may explain the different findings in this study. Studies on the pharmacokinetics of oxprenolol [30] and bufuralol [8] given orally to patients with renal failure, have shown that presystemic elimination is

288

decreased in uraemia. In both studies, elimination half-life was unchanged, and this was attributed to a concomitant decrease in volume of distribution. No changes in cytochrome P-450. The hepatic metabolism of some drugs appears to be unaffected by renal impairment (table II). For example, the total clearance of oral and i.v. metoprolol in patients with varying degrees of renal impairment is the same as that in healthy subjects [46]. Metoprolol is eliminated primarily by hepatic biotransformation, and less than 5 % of a dose given orally is excreted unchanged by the kidneys. As the renal clearance is so small, it can be assumed that the hepatic clearance of metoprolol was unaffected by renal failure. Two studies [26, 79] have shown that the total clearance of i.v. lignocaine is unaffected by renal dysfunction. In both these studies, the uraemic patients were receiving chronic haemodialysis. It is possible that haemodialysis may correct abnormalities of drug metabolism, by removing specific plasma inducers or inhibitors of cytochrome P-450 enzymes. It would be useful, therefore, to know the effect of renal failure on the disposition of lignocaine in patients not receiving haemodialysis. Work on patients receiving regular haemodialysis has shown that the metabolism of codeine, given orally or i.v., is unaffected by renal failure [41]. The metabolism of theophylline, given by continuous i.v. infusion, has also been shown to be normal in patients with renal failure, maintained on haemodialysis [12]. In this study all the patients had chronic airways disease and were smokers, both of which are known to affect hepatic drug metabolism. Although these factors were present in the control group, there were so many variables that interpretation of the results is difficult. Nortriptyline is metabolized extensively by hepatic demethylation and hydroxylation, followed by conjugation. In patients with renal failure, total clearance after a single oral dose was similar to that in a group of healthy controls, and no correlation was seen between total clearance and glomerular filtration rate [29]. This suggests that the metabolism of nortriptyline is unaffected by renal failure, although the effects of renal failure on protein binding were not assessed. This study included both patients receiving haemodialysis and those who were not. Isradipine is a new calcium channel blocker that undergoes extensive hepatic metabolism. No differences in clearance were seen when isradipine was given orally to patients with and without renal failure, suggesting that hepatic biotransformation is unaffected by renal dysfunction [23]. However, there was considerable intersubject variability in this study, so the results must be interpreted with caution. Nisoldipine is another second generation dihydropyridine calcium channel blocker that is eliminated mainly by hepatic metabolism. The oral clearance of nisoldipine in patients with impaired renal function, not receiving haemodialysis, is the same as that in control subjects, indicating that metabolic clearance is unchanged by renal impairment [42]. Work on propafenone [21], a new class I antiarrhythmic agent eliminated primarily by hepatic

BRITISH JOURNAL OF ANAESTHESIA metabolism, has shown that its metabolism is unaffected by renal failure. CONCLUSIONS

Hepatic drug metabolism may be increased, decreased or remain unchanged in patients with renal failure. The exact mechanisms of these changes are unknown, and the effect of renal impairment on the metabolism of a particular drug cannot be predicted from theoretical considerations. For example, nifedipine, nitrendipine and nisoldipine are all apparently metabolized in irivo by the same isoenzyme, cytochrome P-450 3A4, yet renal failure increases the metabolism of nifedipine [19], decreases that of nitrendipine [6] and has no effect on the metabolism of nisoldipine [42]. In the light of the present state of knowledge, it is important to consider the possibility of altered hepatic clearance when prescribing drugs for patients with renal impairment. If the metabolism of a drug is known to increase in renal failure, then the dose may have to be increased in order to achieve the therapeutic effect. Conversely, if the metabolism of a drug decreases in renal failure, then a reduction in dose will be necessary to avoid unwanted effects. If the effect of renal failure on the metabolism of a drug is unknown, then particular care should be taken with drugs that are extensively metabolized in the liver and have a narrow therapeutic index. Unfortunately, measuring the plasma concentration of a drug is only helpful for a small number of drugs such as anticonvulsants, antiarrhythmics and certain antibiotics. This is because, for many drugs, the plasma concentration does not correlate with the concentration of drug at the receptor [16] or the therapeutic effect [18]. The dose of any drug that undergoes significant hepatic metabolism should therefore be titrated carefully against the clinical effect when given to a patient with impaired renal function. Future studies of drug metabolism in renal failure should exclude, as causes of altered hepatic clearance, changes in other pharmacokinetic variables, for example, alterations in protein binding of drugs which are highly protein-bound and changes in hepatic blood flow of drugs with a high extraction ratio. The plasma concentration of metabolites should always be measured to eliminate the effects of metabolite accumulation on hepatic clearance, and the possibility of extrahepatic metabolism should be considered. Future studies should also ensure that the control and study groups are well matched for age, smoking habit and alcohol intake, so that the effects of these factors on hepatic clearance is minimized. Further research is needed to elucidate fully the mechanisms responsible for the changes in hepatic drug metabolism, observed in renal failure. The possibility that different mechanisms operate for different cytochrome P-450 isoenzymes should be investigated. ACKNOWLEDGEMENTS During the preparation of this paper, Dr A. C. Elston was in receipt of a grant from the Addenbrooke's Hospital Trust Fund.

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