Current Drug Metabolism, 2003, 4, 91-103
`
`91
`
`Drug Metabolism in Chronic Renal Failure
`
`Vincent Pichette* and François A. Leblond
`
`Service de néphrologie et Centre de recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Faculté de Médecine,
`Université de Montréal, Québec, Canada
`
`Abstract: Pharmacokinetic studies conducted in patients with CRF demonstrate that the nonrenal clearance of
`multiple drugs is reduced. Although the mechanism by which this occurs is unclear, several studies have shown
`that CRF affects the metabolism of drugs by inhibiting key enzymatic systems in the liver, intestine and kidney.
`The down-regulation of selected isoforms of the hepatic cytochrome P450 (CYP450) has been reported secondary to
`a decrease in gene expression. This is associated with major reductions in metabolism of drugs mediated by
`CYP450. The main hypothesis to explain the decrease in liver CYP450 activity in CRF appears to be the
`accumulation of circulating factors which can modulate CYP450 activity. Liver phase II metabolic reactions are also
`reduced in CRF. On the other hand, intestinal drug disposition is affected in CRF. Increased bioavailability of
`several drugs has been reported in CRF, reflecting decrease in either intestinal first-pass metabolism or extrusion of
`drugs (mediated by P-glycoprotein). Indeed, intestinal CYP450 is also down-regulated secondary to reduced gene
`expression, whereas, decreased intestinal P-glycoprotein activity has been described. Finally, although the kidneys
`play a major role in the excretion of drugs, it has the capacity to metabolize endogenous and exogenous
`compounds. CRF will lead to a decrease in the ability of the kidney to metabolize drugs, but the repercussions on
`the systemic clearance of drugs is still poorly defined, except for selected xenobiotics. In conclusion, reduced drug
`metabolism should be taken into account when evaluating the pharmacokinetics of drugs in patients with CRF.
`
`Key Words: Chronic renal failure, cytochrome P450, gene expression, drug metabolism, intestine, liver, serum mediators,
`P-glycoprotein.
`
`1. INTRODUCTION
`
`(CRF),
`failure
`renal
`The prevalence of chronic
`predominantly due to aging, diabetes, hypertension and renal
`vascular disease, has increased steadily during the last
`decades [1, 2]. The cost of care for these patients has also
`risen progressively
`in part because of excessive or
`inappropriate drug use [3, 4]. Some studies have revealed
`that patients with CRF require an average of more than seven
`drugs to manage the underlying renal disease and their
`comorbid states [3]. Furthermore 40% of patients with
`creatinine clearance of less than 40 mL/min receive drug
`dosages higher (range 1.07-6.45) than required [5]. Both,
`excessive use of drugs and especially inappropriate dosage
`increase the risk of adverse effects, including the risk of
`nephrotoxicity, and increase the cost of care [3, 4, 6]. For
`instance, Johnson and Bootman have estimated
`that
`$US76.6 billion are spent every year to manage drug-related
`morbidity and mortality [7]. Thus, appropriate dosage of
`drugs in CRF is a crucial consideration in avoiding adverse
`effects, minimizing the time and cost of management of
`adverse events, and ensuring optimal patient outcome.
`
`CRF interferes with the elimination of many drugs
`because of the reduction in glomerular filtration rate (GFR),
`
`*Address correspondence to this author at the Centre de recherche Guy-
`Bernier, Hôpital Maisonneuve-Rosemont, 5415 boul. de l’Assomption,
`Montréal, Québec, Canada H1T 2M4; Tel: (514) 252-3489; Fax: (514 255-
`3026; E-mail: vpichette.hmr@ssss.gouv.qc.ca
`
`and tubular secretion [8]. Dose adjustment of drugs excreted
`by the kidney is made according to the GFR. However
`despite dosage adjustment, patients with CRF still present a
`great number of adverse effects [6, 8]. Part of
`this
`phenomenon is related to the fact that CRF also affects the
`nonrenal route of elimination of drugs, i.e. hepatic, intestinal
`and renal metabolism of drugs is decreased in CRF [6, 9-
`14]. It could also be explained by alteration in non-metabolic
`elimination of drugs by the liver and the intestine, i.e. drug
`elimination mediated by P-glycoprotein.
`
`The aim of this article is to review drug metabolic
`disturbances
`in
`renal
`failure, emphasizing on drug
`metabolizing enzymes, particularly cytochrome P450
`(CYP450). The repercussions of renal failure on intestinal
`and liver P-glycoprotein will also be reviewed.
`
`2. LIVER DRUG METABOLISM
`
`2.1. Human Studies
`
`Many investigators have shown, that in patients with
`renal failure there is a decrease in the metabolic clearance of
`numerous drugs. Several reviews have been published on the
`subject [3, 4, 6, 8, 9, 13]. Some of these drugs are presented
`in table 1. The vast majority is metabolized in the liver,
`suggesting that renal failure impedes hepatic biotransfor-
`mation of drugs. Several of the substrates in table 1 are
`eliminated catalyzed by the CYP450, suggesting that hepatic
`CYP450 is altered in CRF [9, 15, 16].
`
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`© 2003 Bentham Science Publishers Ltd.
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`92 Current Drug Metabolism, 2003, Vol. 4, No. 2
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`Pichette and Leblond
`
`Table 1. Effect of Chronic Renal Failure on Nonrenal Clearance (% Change from Normal Clearance)
`
`Acyclovir (62)
`
`Aztreonam (33)
`
`Captopril (50)
`
`Cefmenoxime (45)
`
`Cefonicid (60)
`
`Cefsulodin (52)
`
`Cimetidine (62)
`
`Ciprofloxacin (33)
`
`Codeine (17)
`
`Fluconazole (50)
`
`Imipenem (85)
`
`Metclopramide (66)
`
`Moxalactam (63)
`
`Minoxidil (46)
`
`Nicardipine (37)
`
`Procainamide (61)
`
`Verapamil (54)
`
`Adapted from Lam, Y, W.; Banerji, S.; Hatfield, C. and Talbert, R.L. (1997) Principles of drug administration in renal insufficiency. Clin Pharmacokinet., 32 (1), 30-57. with
`permission from publisher Adis International Ltd.
`
`We are not aware of human studies demonstrating a
`reduction in liver cytochrome P450 isoforms in CRF.
`However, several methods have been described to assess, in
`vivo, the CYP activity in humans and the most widely used
`is the administration of probe drugs that are selectively
`metabolized by specific CYP450 isoforms [17]. Kevorkian
`et al. reported that the use of dextromethorphan or sparteine,
`to assess CYP2D6 activity, was possible in patients with
`CRF [18]. The results of their study revealed that there was a
`decrease in the metabolic clearance of sparteine, suggesting a
`decrease in CYP2D6 activity in CRF patients [18]. Other
`authors have also suggested that CYP2D6 is compromised
`in parallel with the deterioration of renal function in CRF
`patients [19].
`
`There are few studies on liver phase II reactions in CRF.
`Sulfation appears
`to be normal, whereas acetylation
`(isoniazide) and glucuronidation (fluconazole) have been
`reported to be reduced [20-22] (see section 2.2.2).
`
`Although the studies cited above strongly suggest that
`renal failure reduces the metabolism of drugs in CRF
`patients, it is still difficult to predict exactly how renal
`failure will influence the disposition of a specific drug. Part
`of this problem comes from the fact that most clinical
`studies were made
`in conditions where concurrent
`medications, age and smoking habits (all factors known to
`strongly influence CYP450) were not necessarily controlled.
`Furthermore, the severity of the renal failure should be taken
`into account in interpreting pharmacokinetics studies in renal
`failure because some investigators have reported a correlation
`between the decrease in GFR and the decrease in nonrenal
`clearance [6, 23-25]. In addition to the severity, the duration
`of
`the renal failure seems
`to
`influence
`the hepatic
`metabolism. For
`instance,
`the nonrenal clearance of
`imipenem was 50 ml/min in patients with CRF, 95 ml/min
`in patients with acute renal failure (ARF) and 130 ml/min in
`control patients [26].
`
`In summary, renal failure in human is associated with a
`decrease in
`the metabolism of several drugs that are
`preferentially biotransformed by the liver. This decrease in
`biotransformation appears to be related to a reduction in the
`activity of hepatic CYP450, and the importance of this
`phenomenon seems to be related to the severity and the
`duration of renal failure.
`
`2.2. Animal Studies
`
`2.2.1. Cytochrome P450
`
`2.2.1.1. In Vitro Metabolism
`Several studies have looked at the repercussions of
`experimental renal failure on microsomial and cytosolic
`enzyme content of the liver [27-34]. Most of the studies have
`focused on the CYP450 since it is the major enzymatic
`system involved in drug metabolism. The results of these
`studies show that in male rats with CRF, total hepatic
`CYP450 content decreases between 19 to 47%. Moreover,
`significant reductions in enzymatic reactions normally carried
`by the CYP450 have been reported in vitro: N-demethylation
`of erythromycin, aminopyrine and ethylmorphine, O-
`demethylation of codeine and hydroxylation of aniline. There
`is a correlation between the decrease in total CYP450
`activity and the severity of renal failure in rats [30-31, 33,
`34]. We also reported a correlation between the reduction in
`creatinine clearance and the decrease in in vitro metabolism
`of erythromycin [33, 34].
`
`2.2.1.2. CYP450 Protein Expression
`is
`In male adult rat, hepatic cytochrome CYP450
`composed of several isoforms and those involved in drug
`metabolism processes
`include CYP1A2, CYP2C11,
`CYP2D, CYP2E1 and CYP3A1/3A2 [35]. Knowledge of
`which isoforms are decreased in CRF is critical in order to
`predict which drugs are at risk for accumulation. Although
`several studies have focused on the repercussions of CRF on
`total hepatic CYP450 content, only few investigators have
`studied specific CYP450 isoforms. Uchida et al. reported a
`reduction in the levels of hepatic CYP2C6, CYP2C11 and
`CYP3A2 and a slight increase in CYP1A2 in male adult rats
`with CRF [31]. In our laboratory, we described a significant
`reduction in CYP2C11, CYP3A1 and CYP3A2 in male
`adult rats with CRF, while no isoform induction was noted
`(Fig. (1)) [33, 34]. Furthermore, the levels of CYP450
`protein were inversely correlated with the degree of renal
`failure, assessed by the creatinine clearance [33, 34].
`Interestingly, CYP3A1 and 3A2 in the rat correspond to
`CYP3A4 in humans. Since this isoform is responsible for
`the metabolism of multiple drugs commonly used in CRF
`patients, patients with CRF could be at risk for drug
`accumulation and toxicity.
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`Drug Metabolism in Chronic Renal Failure
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`Current Drug Metabolism, 2003, Vol. 4, No. 2 93
`
`Fig. (1). Protein expression of liver CYP450 isoforms in control paired-fed (c) and CRF rats (g). Protein bands are expressed in
`densitometry units (%). The densitometry units of control paired-fed rats were arbitrarily defined as 100%. Data are the mean –
` S.E. of
`six rats in each group.
`
`*P < 0.001 compared with control paired-fed rats.
`
`Reproduced from Leblond, F.A.; Giroux, L.; Villeneuve, J.P. and Pichette, V. (2000) Decreased in vivo metabolism of drugs in chronic
`renal failure. Drug Metab. Dispos., 28(11), 1317-1320 with permission from the American Society for Pharmacology and
`Experimental Therapeutics .
`
`2.2.1.3. In Vivo Metabolism
`is
`In vitro studies clearly demonstrated that CRF
`associated with a down-regulation of
`liver CYP450.
`However, the consequences of
`liver CYP450 decrease
`induced by CRF on the in vivo drug metabolizing capacity
`remain poorly documented. In animals, very few data are
`available on the repercussions of CRF on systemic drug
`metabolism by the liver. A major problem with drug
`disposition studies in rats is that the blood samples used for
`pharmacokinetic analysis can lead to significant blood loss
`and hypovolemia. Uchida et al. studied the changes in
`trimethadione (TMO) metabolism using the microdialysis
`method (avoiding excessive blood samples) in CRF rats
`[31]. They found that the N-demethylation of TMO was
`reduced by 25 % in CRF. However, since TMO N-
`demethylation is catalyzed by several CYP450 isoforms, a
`reduction in its metabolism does not indicate which specific
`isoform is reduced [36]. On the other hand, Tvedegaard et al.
`found no modification in the antipyrine clearance in rabbits
`with CRF [37].
`
`We used breath tests as probes for evaluating in vivo liver
`metabolism in CRF rats. Breath tests have been developed
`as methods to evaluate the catalytic activity of CYP450
`isoenzymes by measuring the rate of demethylation of a drug
`[38]. The formaldehyde generated by CYP450 mediated
`demethylation reactions is rapidly oxidized and excreted as
`carbon dioxide in the breath. The rate of production of 14CO2
`from a suitable radiolabelled substrate reflects the in vivo rate
`of its demethylation and thus the catalytic activity of either a
`subset or a specific cytochrome P450 depending on the
`studied substrate. Various substrates have been used in
`breath tests to evaluate CYP450 activity in vivo in rats and
`humans. The aminopyrine breath test has often been used to
`evaluate liver metabolic function [39, 40]. In vitro and in
`vivo studies suggest that aminopyrine breath tests can be
`used to evaluate the activity of CYP2C11 in the rat [41, 42]
`although other CYP450 isoenzymes also contribute to its
`demethylation, including CYP1A2, 2A2, 2B, and 2D1.
`Caffeine and erythromycin breath tests have also been used
`to measure the liver catalytic activity of CYP1A2 and
`CYP3A2 isoenzymes [42-45].
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`94 Current Drug Metabolism, 2003, Vol. 4, No. 2
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`Pichette and Leblond
`
`In our study, the aminopyrine breath test was used to
`evaluate the activity of CYP2C11; caffeine and erythromycin
`breath tests were used to measure the catalytic activity of
`CYP1A2 and CYP3A2
`isoenzymes,
`respectively. We
`reported that aminopyrine and erythromycin breath tests were
`reduced by 35 % in CRF rats, while the caffeine breath test
`remained unchanged (Fig. (2)) [32]. We also found a
`correlation between the reduction in creatinine clearance and
`the decrease in the in vivo metabolism of drugs. These
`results demonstrate that in rats, CRF is associated with a
`reduction in the metabolism of drugs in vivo, secondary to a
`decrease in selective liver CYP450
`isoforms, namely
`CYP2C11 and CYP3A1/3A2. Whether
`reduction
`in
`extrahepatic metabolism of drugs (e.g. intestinal), that could
`further participate in the reduction of drug metabolism found
`in this study, remains to be defined.
`
`2.2.1.4. CYP450 Gene Expression
`The reduction in liver CYP450 in CRF could be secon-
`dary to a decrease in synthesis or an increase in degradation.
`Our group studied, in the male adult rat, the repercussions of
`CRF on the CYP450 gene expression in the liver [33, 34].
`The results demonstrated that there was an association
`between lower levels of mRNAs and protein expression for
`several isoforms of hepatic cytochrome P450, namely
`CYP2C11, 3A1 and 3A2 [33, 34]. These results strongly
`suggest that CRF leads to a reduction in gene expression of
`liver CYP450
`isoforms. However,
`the mechanisms
`underlying the diminution of liver CYP2C11, 3A1 and 3A2
`gene expression in CRF are not known. Caloric restriction,
`as seen in CRF rats, down-regulates hepatic genes of drug
`metabolizing enzymes in the mouse and in the rat [46, 47].
`However, in our control paired-fed rats we did not observe
`
`Fig. (2). Breath tests with erythromycin (EBT), aminopyrine (ABT), and caffeine (CBT) in control paired-fed (c) and CRF rats (g).
`Values represent the 2-h cumulative 14CO2 output expressed as a percentage of the injected dose. Data are the mean –
` S.E. of six rats in
`each group.
`
`*P < 0.001 compared with control paired-fed rats.
`
`Reproduced from Leblond, F.A.; Giroux, L.; Villeneuve, J.P. and Pichette, V. (2000) Decreased in vivo metabolism of drugs in chronic
`renal failure. Drug Metab. Dispos., 28(11), 1317-1320 with permission from the American Society for Pharmacology and
`Experimental Therapeutics .
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`
`any modification in cytochrome CYP450 levels despite a
`similar weight loss in controls and CRF rats [33, 34].
`
`2.2.1.5. Mechanisms Implicated in Liver CYP450 Activity
`and Expression Down-Regulation
`The mechanism underlying the down-regulation of liver
`CYP450 in CRF remains poorly understood. Leber and
`Schutterle have shown that in CRF, the reduction of liver
`CYP450 induced by CRF could be reversed in part by l-
`aminolevulinic acid but
`these results have not been
`confirmed [27]. It appears excluded that chronic protein
`malnutrition, as seen in CRF, could affect CYP450
`synthesis in the liver [33, 34].
`
`An attractive hypothesis to explain CYP450 activity and
`expression down regulation is the presence of endogenous
`inhibitors in the blood of uremic animals that may modulate
`the activity of CYP450. Terao and Chen have shown, in
`single-pass rat liver perfusion studies, that the extraction of
`L-propranolol was significantly lower in rats with acute renal
`failure compared to control rats [48]. When livers of rats
`with acute renal failure were perfused with blood from
`control rats, the extraction of L-propranolol was similar to
`that of control rats. However, when livers of control rats
`were perfused with blood
`from animals with
`renal
`insufficiency,
`there was a significant decrease
`in L-
`propranolol extraction. Although this study was done in rats
`using an acute renal failure model and reported no data on
`drug metabolizing enzyme, it provided the first evidence for
`the presence of an inhibitory factor in the uremic blood that
`could modify the biotransformation of drugs [48].
`
`The presence of a circulating factor in uremia that inhibits
`liver metabolism has also been implicated in CRF patients.
`Ahmed et al. studied the pharmacokinetics of nicardipine in
`three groups, control subjects, patients with CRF and
`patients undergoing hemodialysis [49]. Plasma clearance of
`nicardipine was reduced in patients with CRF (6.5 –
` 2.6
`ml/min/kg) compared with control subjects (10.4 –
` 3.1
`ml/min/kg) and patients undergoing hemodialysis (12.5 –
`4.6 ml/min/kg). The fact that the clearance of nicardipine
`was identical in control subjects and patients undergoing
`hemodialysis suggest that the inhibitors can be removed by
`dialysis. Further supporting the presence of serum inhibitors,
`it has been shown that incubation of microsomes, prepared
`from healthy human livers, with serum of patients with CRF
`is associated with a decrease
`in
`the metabolism of
`midazolam and
`tolbutamide,
`reflecting CYP3A4 and
`CYP2C9 activities [50].
`
`In order to confirm the presence of serum mediators
`affecting activity and/or expression of the isoforms of hepatic
`CYP450, we recently conducted a study where we incubated
`normal rat hepatocytes with serum from CRF and control
`male adult rats [51]. This study revealed, that in normal
`hepatocytes incubated for 24 hours with serum (concentration
`of 10%) from rats with CRF, total CYP450 level decreased
`by 35% compared to serum from control animals [51]. We
`also showed that protein expression of several CYP450
`isoforms (CYP2C6, 2C11, 3A1 and 3A2) were decreased by
`more than 35% in normal hepatocytes incubated with serum
`from CRF rats (Fig. (3)). The decrease in protein expression
`of CYP450 isoforms mediated by serum from rats with CRF
`
`was secondary to reduced gene expression (Fig. (4)).
`Although the mechanisms responsible for the diminished
`hepatic gene expression in CRF are not known, the present
`study suggests that uremic mediator(s) may affect CYP450
`promoters.
`
`A number of studies indicate that animals with CRF
`display
`impaired protein synthesis, by
`reduced gene
`expression in
`the liver,
`the skeletal muscle, and
`the
`cardiomyocytes [52-54]. For instance, the mRNA of hepatic
`lipase and insulin-like growth factor 1 receptor are decreased
`in hepatocytes and skeletal muscle of rats with CRF,
`respectively [52-54]. CRF is associated with sustained
`elevations in calcium in many cell types, including the
`hepatocytes. This high intracellular calcium seems to be a
`major factor underlying cell reduced protein synthesis [55,
`56]. It has been suggested that the increase in basal [Ca2+]i of
`hepatocytes was secondary to parathyroid hormone (PTH)
`elevation that accompanies CRF [57]. The predominant
`pathway for the PTH-induced increase in [Ca2+]i is the
`stimulation of a G protein-adenylate cyclase-cAMP system,
`which leads to stimulation of a calcium transport system
`[57]. On the other hand, cAMP has been shown to down-
`regulate CYP450 [58]. We recently demonstrated that the
`molecular weight of the mediator(s) present in uremic serum
`is between 10 and 30 kDa. Since rat PTH molecular weight
`is around 10 kDa , it could be a potential mediator of hepatic
`CYP450 down-regulation in CRF [51].
`
`Other potential uremic serum mediators implicated in the
`down-regulation of liver CYP450 are cytokines, since their
`molecular weight averages 20 kDa. Several studies have
`demonstrated that CRF
`is associated with a chronic
`activation of inflammatory response and patients with CRF
`present an increase in plasma levels of many cytokines [59-
`63]. On the other hand, cytokines are able to down-regulate
`hepatic CYP450 in vitro and in vivo [64-66].
`
`In summary, animal studies demonstrate that CRF is
`associated with a decrease in the expression of liver CYP450
`isoforms secondary
`to
`reduced mRNA
`levels. Drug
`metabolism activity, assessed by several oxidative reactions,
`normally carried out by the CYP450 is also depressed in rats
`with CRF. Hepatic CYP450 down-regulation is correlated
`with the degree of renal failure. We may speculate that this
`down-regulation could explain
`the reduction
`in drug
`metabolism observed in patients with CRF, since rat
`CYP3A1 and 3A2 correspond to CYP3A4 in humans which
`is responsible for the metabolism of many drugs commonly
`used in patients with CRF. The main hypothesis for
`decreased CYP450 activity and expression appears to be the
`presence of uremic factors that accumulate in CRF.
`
`2.2.2. Phase II Reactions
`Phase II reactions in CRF have not been studied as
`extensively as phase I reactions. Several human studies have
`shown that conjugation reactions can be altered in CRF.
`Singlas et al. studied the disposition of zidovudine in
`patients with CRF, drug eliminated by glucuronidation
`(75%), and renal excretion (25%), and demonstrated that
`zidovudine AUC was significantly higher in patients with
`CRF than in patients without renal failure [20]. Since the
`increase in AUC could not be explained solely by the
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`Fig. (3). Protein expression of hepatic cytochrome P450 isoforms in hepatocytes incubated with serum from control (c) and CRF
`rats (g). Protein bands are expressed in densitometry units (%). The densitometry units of control rats were arbitrarily defined as
`100%. Data are the mean –
` SEM of 8 experiments in each group.
` *P < 0.01 as compared to serum from control.
`
`Reproduced from Guevin, C.; Michaud, J.; Naud, J.; Leblond, F.A. and Pichette, V. (2002) Down-regulation of hepatic cytochrome
`P450 in chronic renal failure: role of uremic mediators. Br. J. Pharmacol., 137(7), 1039-1046. with permission from publisher Nature
`Publishing group .
`
`decrease in the urinary clearance, it has been suggested that
`there was a reduction in the metabolism of zidovudine.
`Several studies have examined the effect of CRF on
`metoclopramide metabolism, which is primarily mediated
`through
`conjugation
`reactions
`(glucuronidation
`and
`sulfation). Baterman et al. found a 30% reduction in the
`clearance of metoclopramide in patients with renal failure
`compared with healthy volunteers [67]. Similar results have
`been shown by Lehmann et al. [68]. Acetylation also appears
`to be reduced in patients with CRF; several reports have
`demonstrated that the metabolic clearance of procainamide is
`reduced by approximately 60% in renal failure [4, 69, 70].
`
`Moreover, a decrease in the acetylation of isoniazide has also
`been reported in patients with CRF [22].
`
`The mechanism leading to a decrease in phase II
`enzymatic reactions is unknown. Very few in vitro studies
`have been done. Paterson and Cohn studied the uridine
`diphosphate
`(UDP)-glucuronyl
`transferase activity
`in
`microsomes from control and rats with CRF and reported a
`19% reduction
`in UDP-glucuronyl
`transferase activity,
`although this difference was not significant (p=0.06) [30].
`On the other hand, Taburet et al. reported that incubation of
`microsomes, prepared from healthy human livers, with
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`
`Fig. (4). mRNA encoding hepatic cytochrome P450 isoforms (CYP2C11, CYP2D and 3A2) in hepatocytes incubated with serum from
`control (c) and CRF rats (g). mRNA bands are expressed in standardised densitometry units (%). The densitometry values for
`cytochrome P450 isoforms were standardised by dividing these values by the values for 18S ribosomal RNA. The standardised
`densitometry units of control rats were arbitrarily defined as 100%. Data are the mean –
` SEM of 8 experiments in each group.
`*P < 0.005 as compared to serum from control rats.
`
`Reproduced from Guevin, C.; Michaud, J.; Naud, J.; Leblond, F.A. and Pichette, V. (2002) Down-regulation of hepatic cytochrome
`P450 in chronic renal failure: role of uremic mediators. Br. J. Pharmacol., 137(7), 1039-1046. with permission from publisher Nature
`Publishing group .
`
`serum of patients with CRF was associated with a decrease
`in the metabolism of zidovudine, reflecting an inhibition of
`UDP-glucuronyl
`transferase [50]. As demonstrated for
`hepatic CYP450, these data strongly suggest the presence of
`serum factors in the blood of patients with CRF that could
`not only down-regulate liver CYP450, but also other
`enzymatic reactions implicated in the metabolism of drugs,
`such as glucuronidation and acetylation.
`
`3. INTESTINAL DRUG METABOLISM
`
`in drug
`role
`liver plays a major
`the
`Although
`metabolism, enzymes that contribute to the metabolism of
`
`drugs are also present at other sites, particularly in the
`intestine [71, 72]. The predominant biotransformation
`system in the intestine is the cytochrome P450 [73]. The
`intestine contains several isoforms of the families CYP1A,
`CYP2B, CYP2C, CYP2D and CYP3A [72-74]. The ability
`of these CYP450 isoforms to metabolize drugs is as
`important as that of the liver. More importantly, small
`intestinal CYP450 provides the principal, initial source of
`biotransformation for
`ingested oral xenobiotics. Small
`intestinal CYP450 is implicated in the phenomenon of first-
`pass metabolism which prevents the absorption of drugs
`[75]. Thus, any modification in intestinal CYP450 could
`have important repercussions on the bioavailability of
`xenobiotics [75].
`
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`98 Current Drug Metabolism, 2003, Vol. 4, No. 2
`
`Pichette and Leblond
`
`Several studies have been conducted to assess the effect of
`CRF on the bioavailability of drugs, and have documented
`that
`the bioavailability
`of
`propranolol,
`tolamolol,
`dihydrocodeine,
`dextropropoxyphene,
`oxprenolol,
`erythromycin, and tacrolimus is increased in patients with
`CRF [3, 6, 76-79]. These observations indicate that in
`patients with CRF, presystemic or first-pass metabolism of
`selected drugs is reduced. Since some of these drugs (e.g.
`propranolol,
`dextropropoxyphene,
`tacrolimus,
`and
`erythromycin) are subject to intestinal first-pass metabolism,
`it is likely that CRF also diminishes intestinal metabolism
`[6, 11]. In the case of tolamolol, CRF increases its
`availability without affecting its half-life, strongly suggesting
`that CRF reduces its intestinal first-pass [80].
`
`that CRF could modify
`Supporting the hypothesis
`intestinal metabolism of drugs, a number of studies indicate
`
`that other intestinal functions could be altered in CRF.
`Several enzymatic reactions carried out by the intestinal
`mucosa have been shown to be decreased in rats with CRF.
`For instance, sucrase and maltase activities are significantly
`reduced, while the activities of other dipeptidases remain
`unchanged [81]. More recently, Vaziri et al. reported that
`enteric xanthine oxidase activity was diminished in animals
`with CRF [82].
`
`Recently, we have studied the repercussions of CRF on
`intestinal CYP450 [83]. Our results revealed a major
`reduction in total intestinal CYP450 in CRF male adult rats,
`with significant decrease in protein expression of selective
`isoforms, namely CYP1A1 and 3A2 (Fig. (5)) [83]. Our
`results also demonstrated that there was an association
`between lower levels of mRNAs and protein for CYP1A1
`and CYP3A2 isoform suggesting that there is reduced gene
`
`Fig. (5). Protein expression of intestinal cytochrome P450 isoforms in control (c) and CRF rats (g). Protein bands are expressed in
`densitometry units (%). The densitometry units of control paired-fed rats were arbitrarily defined as 100%. Data are the mean –
` SD of
`20 rats in each group.
`*P = 8x10-6 and ** P = 2x10-8 as compared to control rats.
`
`Reproduced from Leblond, F.A.; Petrucci, M.; Dube. P.; Bernier, G.; Bonnardeaux, A. and Pichette, V. (2002) Down-regulation of
`intestinal cytochrome P450 in chronic renal failure. J. Am. Soc. Nephrol., 13(6), 1579-1585. with permission from publisher
`Lippincott Williams & Wilkins.
`
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`Drug Metabolism in Chronic Renal Failure
`
`Current Drug Metabolism, 2003, Vol. 4, No. 2 99
`
`expression. The metabolic consequences are important since
`we observed a 30 % decrease in the in vitro metabolism of
`substrate mediated by these two isoforms [83]. Interestingly,
`CYP1A1 and CYP3A1/3A2
`in
`the rat correspond to
`CYP1A1 and CYP3A4 in humans. Since these isoforms are
`responsible for the metabolism of several drugs commonly
`used in CRF, patients could be at risk for drug accumulation
`and toxicity. Indeed, these results could explain why the
`bioavailability of erythromycin and
`tacrolimus
`(both
`metabolized by CYP3A family in the intestine) are increased
`by more than 30 % in CRF patients [78, 79].
`
`In summary, several pharmacokinetic studies conducted
`in human demonstrate that the bioavailability of selected
`drugs is increased in patients with CRF. Although the
`mechanism is still unclear, it appears that this phenomenon
`can be related to decreased intestinal first-pass metabolism.
`Indeed, as happens in the liver, CRF decreases intestinal
`CYP450. Whether uremic circulating factors are also
`implicated in the down-regulation of intestinal CYP450
`remains to be defined.
`
`4. RENAL DRUG METABOLISM
`
`Enzymes involved in the metabolism of drugs are also
`present in the kidneys [13, 72, 84]. Several CYP450
`isoforms have been identified in the kidney from studies of
`enzyme activities and also by molecular biology techniques
`[84]. Although the ability of these isoforms to metabolize
`xenobiotics has been confirmed in vitro [84], the role of
`renal CYP450 in the systemic metabolism of drugs has not
`been documented. However, a reduction in functional renal
`mass, as seen in CRF, should theoretically lead to a decrease
`in the metabolic capacity of the kidney mediated by CYP450
`isoforms.
`
`Enzymes involved in phase II reactions are also present in
`the kidney, particularly those implicated in conjugation
`reactions, such as UDP-glucuronyl-transferases, glutathione
`S-transferases, and N-sulphotransferases [13, 72, 84]. Some
`of these enzymes, particularly UDP-glucuronyl-transferases,
`have a high activity in the kidney, predominantly in the
`proximal tubule [72]. Interestingly, such a location allows
`the kidney to be exposed to the greatest quantity of drugs
`since the proximal tubule is subjected to the bulk of
`glomerular ultrafiltrate and also the highest concentration of
`drugs on the contraluminal side. In vitro studies using either
`isolated perfused
`tubules or perfused kidneys have
`demonstrated that the kidney has the ability to biotransform
`several drugs: paracetamol, morphine,
`sulindac, and
`furosemide. However, few in vivo studies have been
`performed to compare the ability of the kidney to metabolize
`xenobiotics with that of other organs, e.g. the liver or the
`intestine [85]. Furthermore, the contribution of the kidney to
`the systemic metabolism has been poorly documented [85].
`
`The contribution of the kidney to the metabolism of
`furosemide, was studied