The Effect of Chronic Renal Failure on Hepatic Drug
`Metabolism and Drug Disposition
`
`Albert W. Dreisbach*,† and Juan J. L. Lertora†
`
`*Division of Nephrology, Department of Medicine, and †Division of Clinical Pharmacology, Department
`of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
`
`ABSTRACT
`
`There is abundant evidence that chronic renal failure (CRF)
`and end-stage renal disease (ESRD) alter drug disposition by
`affecting protein and tissue binding and reducing systemic
`clearance of renally cleared drugs. What is not fully appreciated
`is that CRF can significantly reduce nonrenal clearance and
`alter the bioavailability of drugs predominantly metabolized by
`the liver. Animal studies in CRF have shown a major down-
`regulation (40–85%) of hepatic cytochrome P-450 metabolism
`involving specific isozymes. Phase II reactions such as acety-
`lation and glucuronidation are also involved, with some
`isozymes showing induction and others inhibition. Hepatic
`
`enzymes exhibiting genetic polymorphisms such as N-acetyl-
`transferase-2 (NAT-2), which is responsible for the rapid and
`slow acetylator phenotypes, have been shown to be inhibited by
`ESRD and reversed by transplantation. There is some evidence
`pointing to the possibility of inhibitory factors circulating in the
`serum in ESRD patients which may be dialyzable. This review
`includes all significant animal and clinical studies using the
`search terms ‘‘chronic renal failure,’’ ‘‘cytochrome P-450,’’ and
`‘‘liver metabolism’’ over the past 10 years obtained from the
`National Library of Medicine MEDLINE database, including
`relevant articles back to 1969.
`
`There is a tacit assumption that the clearance and
`distribution of drugs that are removed from plasma
`exclusively by hepatic metabolism are not affected by
`chronic renal failure (CRF). Therefore no dose adjust-
`ments are necessary in hepatically cleared drugs in this
`population. This is a widespread misconception, primar-
`ily due to a lack of information, which is not supported
`by investigations spanning several decades. The purpose
`of this review is to outline the different ways in which
`drug disposition is altered by CRF, cite specific drugs of
`clinical concern, and discuss proposed mechanisms.
`Citations were derived from MEDLINE (1990–2001)
`using the search terms ‘‘liver metabolism,’’ ‘‘chronic
`renal failure,’’ and ‘‘cytochrome P-450’’ including other
`relevant articles dating back to 1969.
`
`Background Pharmacokinetics
`
`In order to understand the various effects of CRF on
`drug disposition it may be helpful to review some basic
`pharmacokinetic
`concepts
`(1). Systemic
`clearance
`(CLSYS) is equal to the sum of renal (CLR) and nonrenal
`(CLNR) clearances:
`CLSYS ¼ CLR þ CLNR
`
`ð1Þ
`
`Address correspondence to: Albert W. Dreisbach, MD,
`Division of Nephrology, SL45, Department of Medicine,
`Tulane University School of Medicine, 1430 Tulane Ave.,
`New Orleans, LA 70112, or email: adreisb@tulane.edu.
`Seminars in Dialysis—Vol 16, No 1 (January–February) 2003
`pp. 45–50
`
`45
`
`Renal clearance is defined as the amount of drug
`eliminated per unit time in the final urine normalized to
`plasma concentration:
`ð2Þ
`CLR ¼ UV=P;
`where U is the urine concentration, P is the plasma
`concentration, and V is the urine flow rate.
`Renal drug metabolism according to this definition is
`not a component of CLR, but rather is incorporated into
`the nonrenal clearance term CLNR. The renal cyto-
`chrome P-450 activity is 20% of the hepatic cytochrome
`P-450 activity per gram of tissue and the kidney
`participates in conjugation reactions as well
`(2,3).
`However, the total renal mass is one-fifth of the hepatic
`mass and therefore renal cytochrome P-450 may contri-
`butes a minor fraction of the total activity. Nevertheless,
`for drugs which are highly extracted by the kidney and
`whose metabolism is therefore blood flow limited, the
`kidney may play a more significant role, since renal blood
`flow is three- to fivefold greater than hepatic blood flow
`per gram of tissue (4). Of course, this renal drug
`metabolizing capacity deteriorates with the progression
`of CRF, leading to a reduction in nonrenal clearance
`independent of any effects on the liver or intestinal
`metabolism.
`Nonrenal clearance and the distribution volume of
`drugs is altered by CRF via changes in hepatic clearance,
`plasma protein binding, and tissue binding. CRF
`has been shown to decrease plasma protein binding of
`acidic drugs, increasing the free (unbound) fraction (fu),
`as shown in Table 1 (5–18). The mechanism is presum-
`ably the reduction of the apparent binding affinity to
`albumin due to conformational changes in albumin or
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`46
`
`Dreisbach and Lertora
`
`competition with unmeasured small molecules and
`accumulated metabolites that are not entirely removed
`by dialysis (19,20).
`CRF increases plasma levels of a1-acid glycoprotein
`which is induced in acute and chronic inflammation. The
`a1-acid glycoprotein binds basic drugs and one would
`predict increased binding of these drugs in CRF.
`However, in most cases drug binding is reduced or
`remains unchanged and is only occasionally increased, as
`shown in Table 1 (6). The reduced binding of basic drugs
`to a1-acid glycoprotein may result from mechanisms
`similar to those that impair the binding of acidic drugs to
`albumin, such as reduced binding affinity and competing
`ligands circulating in the plasma of end-stage renal
`disease (ESRD) patients.
`CRF has also been shown to decrease the distribution
`volume (Vd) of drugs such as digoxin, which has its Vd
`reduced by 50% in ESRD due to reduced tissue binding
`(2). The opposite effect is observed with phenytoin, which
`shows a twofold increase in Vd in ESRD due to reduced
`plasma protein binding (2). Furthermore, CRF reduces
`hepatic clearance of drugs by mechanisms which will be
`discussed later.
`The determinants of hepatic clearance will be better
`understood after a further discussion of clearance
`concepts (1,21). The rate of extraction of a drug across
`an organ of elimination is described by the blood flow
`through the organ (Q) and the concentrations of the drug
`at the arterial side (input) (CA) and at the venous side
`(output) (CV) as shown in the equation 3. Extraction
`ratio (E) is the rate of extraction divided by the rate of
`presentation (equation 4). Clearance (CL) is the rate of
`extraction normalized to CA (equation 5). Hepatic
`clearance (CLH) is equal to hepatic blood flow multiplied
`by EH (equation 6).
`Rate of extraction ¼ QðCA CVÞ
`E ¼ rate of extraction=rate of presentation
`¼ CA CV=CA
`CL ¼ rate of extraction=CA
`¼ QðCA CVÞ=CA
`
`ð3Þ
`
`ð4Þ
`
`ð5Þ
`
`TABLE 1. Drugs with changes in protein binding in CRF
`
`Drug type
`
`Change in binding
`
`Acidic
`Desmethyldiazepam
`Phenytoin
`Valproic acid
`Salicylate
`Phenylbutazone
`Furosemide
`Warfarin
`Sulfamethoxazole
`
`Basic
`Disopyramide
`Vancomycin
`Morphine
`Oxazepam
`
`Adapted from Refs. 5 and 6.
`
`Decreased
`Decreased
`Decreased
`Decreased
`Decreased
`Decreased
`Decreased
`Decreased
`
`Increased
`Decreased
`Decreased
`Decreased
`
`ð6Þ
`CLH ¼ QEH
`If a drug has a high hepatic extraction ratio, E
`approaches one, then the total hepatic clearance (CLH) is
`rate limited by hepatic blood flow. With a low-extraction
`drug, E approaches zero, then total hepatic clearance is
`rate limited by intrinsic (unbound) clearance (CLINT)
`and free fraction (fu) of drug. The relationship between
`these parameters is expressed in the well-stirred model of
`total hepatic clearance (CLHTOT) (equation 7) (21):
`ð7Þ
`CLHTOT ¼ QCLINTfu=Q þ CLINTfu:
`Intrinsic hepatic clearance relates the rate of metabo-
`lism at steady state to the free unbound fraction in blood.
`If the drug is highly extracted, we assume CLINTfu>>Q,
`then CLHTOT ¼ Q and total hepatic clearance is blood
`flow limited and relatively independent of changes in
`intrinsic hepatic clearance which may be produced by a
`down-regulation or induction of hepatic cytochrome
`P-450. If the drug is a low-extraction agent then we
`assume Q>>CLINTfu, then CLHTOT ¼ CLINTfu and
`would be highly influenced by changes in plasma protein
`binding and intrinsic hepatic clearance. These various
`permutations have been aptly simulated using empiric-
`ally derived models (22). Hepatic blood plasma flow has
`been shown to be unaffected by CRF (23). However,
`concomitant diseases such as congestive heart failure and
`chronic liver disease are frequently associated with ESRD
`and are known to reduce hepatic blood flow and CLHTOT.
`For a highly extracted drug, orally administered, with
`a large first-pass effect (presystemic clearance) and low
`systemic bioavailability (F), the magnitude of the first-
`pass effect can be estimated by equation 8 (1,21):
`F ¼ QH=QH þ CLINTfu:
`ð8Þ
`For highly extracted drugs, CLINTfu>>QH, then
`F ¼ QH/CLINTfu. Therefore changes in intrinsic hepatic
`clearance and plasma protein binding induced by CRF
`would be predicted to produce significant changes in
`systemic bioavailability. For example, a reduction in
`intrinsic hepatic clearance would reduce first-pass meta-
`bolism, causing a sizable increase in bioavailability of a
`highly extracted drug, leading to a clinically significant
`increase in steady-state plasma concentration.
`In summary, CRF can significantly affect the dispo-
`sition of both low and high hepatic extraction drugs
`which are cleared predominantly by the liver (Table 2).
`Hepatic clearance of low-extraction drugs is limited by
`intrinsic hepatic clearance and plasma protein binding.
`A reduction in intrinsic hepatic clearance will lead to
`reduced systemic clearance and produce an increase in
`steady-state plasma levels for both free and total drug
`concentrations of low-extraction drugs. Reduced plasma
`protein binding leading to increased free fraction (fu)
`will also produce an elevated total hepatic clearance
`that leads to a reduction in total steady-state drug
`concentrations but no change in free concentrations as
`long as intrinsic hepatic clearance is unchanged. Since
`free concentrations are presumably the biologically
`active fraction, then the result may have little clinical
`impact.
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`CRF AND DRUG METABOLISM
`
`47
`
`TABLE 2. Summary of the effects of CRF on pharmacokinetic parameters
`
`Low hepatic extraction drugs (EH < 0.20)
`Cytochrome P-450 down-regulation, circulating inhibitors fi CLINTfl fi CLTOTHEPflCT›Cu›
`(Acidic drugs) fi PPBfl fi CLTOTHEP›CTflCu«
`High hepatic extraction drugs (EH > 0.80)
`Cytochrome P-450 down-regulation, circulating inhibitors fi CLINTfl fi F›
`(Acidic drugs) fi PPBfl fi Ffl
`
`Hepatic extraction, EH; total hepatic clearance, CLTOTHEP; total steady-state plasma concentration, CT; free steady-state plasma
`concentration, Cu; intrinsic hepatic clearance, CLINT; plasma protein binding, PPB; bioavailability, F.
`
`For high-extraction drugs, total hepatic clearance is
`blood flow limited. Since hepatic blood flow is not altered
`in renal failure, total systemic clearance should not be
`affected by changes in intrinsic hepatic clearance or
`plasma protein binding. However, first-pass metabolism
`(presystemic clearance) is a function of CLINT and fu, so
`changes in these parameters will result in significant
`changes in systemic bioavailability, as much as several
`fold for high-extraction drugs.
`
`Animal Studies: Effect of Renal Failure
`on Cytochrome P-450 Metabolism
`
`Acute Renal Failure Models
`
`Animal studies spanning several decades have shown
`reduced hepatic microsomal enzyme activity in experi-
`mental models of acute and chronic renal failure. In rats
`with acute renal failure (ARF) (produced by subtotal
`nephrectomy), hepatic microsomal protein content (per
`gram of liver) was reduced (24). Demethylation of
`aminopyrine and p-nitroanisole, and para-hydroxyla-
`tion of acetanilide also dropped by 30–50%. There was
`stimulation of O-demethylation of p-nitroanisole by
`injections of d-aminolevulinic
`125%. Intraperitoneal
`acid normalized total microsomal protein cytochrome
`P-450 content but did not reverse the inhibition of
`cytochrome P-450 activity. In other rat models of ARF
`(induced by bilateral ureteral ligation or uranylnitrate
`injection), a reduction of aminopyrine N-demethylation
`was seen (25). Total cytochrome P-450 and aniline
`hydroxylation was reduced as well, but did not reach
`statistical significance.
`An example of how the pharmacokinetics of a highly
`extracted, extensively metabolized drug can be altered by
`experimental renal failure in the intact rat is illustrated by
`the following study using a rat model in which ARF is
`induced by uranyl nitrate (26). Following injection of
`ARF rats and controls with intravenous levoproprano-
`lol, no differences in the area under the plasma drug
`concentration versus time curve (AUC) or plasma
`clearance were seen. Using the same protocol with oral
`levopropranolol,
`the ARF rats showed a 2.5-fold
`increase in systemic bioavailability from 7 to 18%. The
`same investigators then studied levopropranolol first-
`pass metabolism in isolated perfused rat liver (27). Liver
`from normal rats perfused with normal blood yielded a
`97.4% extraction (EH) of levopropranolol. Livers from
`ARF rats perfused with uremic blood yielded a levopro-
`pranolol extraction of 90.6%. This resulted in a greater
`than threefold increase in bioavailability (F) (2.6–9.4%)
`consistent with the data from intact animals and
`
`corresponding to a 50% drop in CLINT. When livers
`from normal rats were cross-perfused with uremic blood,
`EH was reduced to 92.7%, not significantly different
`from the uremic livers perfused with uremic blood.
`Surprisingly, uremic livers cross-perfused with normal
`blood showed an EH of 97.0%, identical to the control
`normal livers perfused with normal blood. These data
`suggest that cytochrome P-450 metabolism of propran-
`olol in uremic rats is not down-regulated but that a
`rapidly acting inhibitory factor exists in uremic serum.
`
`Chronic Renal Failure Models
`
`A study utilizing a CRF rat model induced by subtotal
`nephrectomy showed a 24–32% decrease in hepatic
`N- and O-demethylation activities, whereas S-deme-
`thylase, esterase, UDP-glucuronyl
`transferase, and
`monoamine oxidase were not altered (28). Alcohol
`dehydrogenase activity increased by 71% and cyto-
`chrome P-450 levels decreased by 26%. CRF also
`increased hexobarbital sleeping time. In each case
`alterations correlated with extent of CRF.
`Over the past 15 years the cytochrome P-450 gene
`superfamily has been sequenced and various isozymes
`and isozyme-specific probe drugs have been identified. In
`a CRF model in rats using subtotal nephrectomy, the
`effect of CRF on the activity of various cytochrome
`P-450 isozymes, in vivo, was investigated using 14C-labe-
`led caffeine (CYP1A2), aminopyrine (CYP2C11), and
`erythromycin (CYP3A2) breath tests (29). There was a
`35% reduction in CYP2C11 and CYP3A2 activities and
`no difference in CYP1A2 as measured by their respective
`breath tests. Total cytochrome P-450 was reduced by
`40% and protein expression of CYP2C11, CYP3A1, and
`CYP3A2 in CRF rats was reduced by 45%, 85%, and
`45%, respectively; CYP1A2 did not change. There was
`also a significant correlation between cytochrome P-450
`activity measured by breath tests and protein expression
`of the various cytochrome P-450 isozymes.
`A later study by the same investigators also confirmed
`these findings (30). Protein expression of CYP2C6,
`CYP2D, and CYPE1 also remained constant. Northern
`blot analysis showed a down-regulation in gene expres-
`sion in CYP2C11, CYP3A1, and CYP3A2 with no
`change in the expression of the remaining cytochrome
`P-450 isozymes tested. Phenobarbital and dexametha-
`sone maintained their ability to induce CYP3A1 and
`CYP3A2 isozymes. Demethylation of erythromycin
`(CYP3A2) was reduced by CRF, which was reversed
`by treatment with phenobarbital and dexamethasone.
`In a CRF model (45 days of severe uremia in rats
`caused by subtotal nephrectomy), no induction of
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`48
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`Dreisbach and Lertora
`
`microsomal cytochrome P-450 enzymes occurred (31).
`However, induction of the phase II reaction, glucuron-
`idation, did occur (77% increase in activity). Total
`cytochrome P-450 content (in nmol/mg of protein) was
`reduced by 45%. P-nitroanisole activity was reduced by
`40%, aminopyrine by 35%, and acetanilide by 40%.
`Treatment with the plasticizer di(2-ethylhexyl)phthalate
`caused a 54% increase in liver wet weight and 65%
`increase in microsomal protein content, a 23% increase
`of demethylation of aminopyrine and a threefold
`reduction in hexobarbital sleeping time in CRF rats but
`not in sham-operated controls. These results and those of
`the previous study (30) suggest that known enzyme
`inducers can partially reverse the effects of CRF on
`hepatic cytochrome P-450 metabolism and that phase II
`reactions such as glucuronidation are relatively preserved
`and in some cases stimulated by CRF.
`In summary, various animal models of ARF and CRF
`have shown reduced activity of hepatic cytochrome
`P-450 in which certain pathways appear to be affected
`and others remain intact. Later studies have shown that
`certain cytochrome P-450 isozymes are down-regulated
`and that reduced protein expression correlates with
`reduced cytochrome P-450 activity measured by specific
`probes, while the expression of other isozymes and their
`activity remains unchanged. Surprisingly levoproprano-
`lol hepatic extraction is inhibited by uremic blood in
`perfused normal rat liver. Uremic livers showed no
`impairment in hepatic first pass when perfused with
`normal blood, suggesting a rapidly acting circulating
`competitive inhibitor of cytochrome P-450 activity
`without down-regulation of cytochrome P-450 expres-
`sion in the uremic liver. This is consistent with the finding
`that CYP2D6, the isozyme that metabolizes levopro-
`pranolol, is not down-regulated in rat CRF models and
`suggests that two mechanisms may explain the reduced
`cytochrome P-450 activity: circulating factors and
`decreased protein expression. Some phase II reactions
`such as glucuronidation appear to be stimulated in CRF.
`The mechanisms for these phenomena have not been
`elucidated.
`
`Clinical Investigations: Effect of CRF on Drug
`Disposition
`
`A number of reviews on the effect of CRF on drug
`disposition exist in the literature (2,4,5,32–34). One of the
`earliest clinical studies showed a reduction in the
`nonrenal elimination (acetylation) of sulfisoxazole given
`intravenously to patients with CRF and questioned the
`concept of therapeutics prevalent in the 1960s that
`azotemic patients should receive the usual doses of drugs
`eliminated by hepatic metabolism (34,35). A later review
`showed decreased reduction, acetylation, and hydrolysis
`reactions but preserved sulfation, glucuronidation, and
`oxidation reactions (34).
`Clinical data exist showing significant alterations
`in nonrenal clearance in CRF for a number of drugs
`(Table 3) (36–61). The majority of these studies involve
`ESRD patients; a few included subjects with moderate to
`severe CRF. These alterations include both substantial
`
`TABLE 3. Effect of CRF on nonrenal clearance
`
`Drug
`
`Increased
`Phenytoin
`Fosinopril
`Bumetanide
`
`Decreased
`Acyclovir
`Aztreonam
`Cefotaxime
`Cilastin
`Imipenem
`Moxalactam
`Captopril
`Procainamide
`Nimodipine
`Verapamil
`Metoclopramide
`Desmethyldiazepam
`Warfarin
`
`NA, not available.
`
`Change in
`nonrenal clearance (%)
`
`Metabolism
`
`57
`70
`57
`
`50
`33
`40
`92
`58
`63
`50
`60
`87
`54
`66
`63
`50
`
`CYP2C9, 2C19
`NA
`NA
`
`NA
`NA
`NA
`NA
`NA
`NA
`Sulfoxidation
`NAT-2
`CYP3A4
`CYP3A4
`CYP2D6
`CYP2C9
`CYP2C9
`
`TABLE 4. Effect of CRF on bioavailability
`
`Propranolol
`Erythromycin
`Tacrolimus
`Propoxyphene
`
`Increased
`Increased
`Increased
`Increased
`
`reductions and increases (36,39) in nonrenal clearance
`ranging from 30 to 90%. In the case of phenytoin, the
`50% increase in total hepatic clearance is produced by a
`two- to threefold increase in free fraction (fu ¼ 20–30%)
`due to reduced plasma protein binding (normal
`fu ¼ 10%) (10,36). This results in a reduction in steady-
`state total phenytoin concentration to 5–10 lg/ml with
`no change in free concentration (1–2 lg/ml) because
`intrinsic hepatic clearance is not altered. Increasing the
`dose of phenytoin to achieve a target concentration of
`10–20 lg/ml for total phenytoin may raise free concen-
`trations to toxic levels.
`For high-extraction drugs, the effect of CRF is
`manifest as an increase in bioavailability (F), as shown
`in Table 4 (36,61–64). The plasma AUC of propoxy-
`phene was increased twofold in ESRD (61). For
`erythromycin, CRF results in a fourfold increase in
`plasma AUC after an oral dose (62,63). Half-life is
`unchanged and Vd is increased in renal failure, suggesting
`that the increase in AUC was due to an increase in F
`because of reduced hepatic uptake.
`In patients with CRF approaching ESRD, oral
`propranolol showed a bioavailability of 62%, compared
`with 32% in ESRD patients on hemodialysis and 19% in
`healthy volunteers (64). This is in agreement with the
`previous animal data showing an increase in F for
`propranolol
`in uremic rats and consistent with the
`pharmacokinetic principle that the bioavailability of high
`hepatic extraction drugs is increased with reductions in
`intrinsic hepatic clearance. The same investigators also
`found that the bioavailability of propranolol was greater
`on the day of dialysis (43%) compared to the day after
`dialysis (34%). These findings are in agreement with the
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`CRF AND DRUG METABOLISM
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`49
`
`animal data in isolated perfused livers which suggest that
`a circulating dialyzable inhibitory factor is present in
`uremic serum. However, another investigator found no
`significant difference in apparent oral clearance, total
`clearance, or bioavailability of propranolol in stable
`renal
`failure patients with creatinine clearance of
`approximately 15 ml/min (65). It is possible that in these
`patients there is enough residual renal function to
`prevent the inhibition of hepatic metabolism.
`Zidovudine is eliminated primarily by glucuronidation
`and 25% is excreted unchanged by the kidneys. The
`plasma AUC was doubled in the CRF group receiving a
`single 200 mg oral dose, indicating a decrease in intrinsic
`hepatic clearance, suggesting that hepatic conjugation
`reactions can be reduced in CRF (66).
`is also
`Another conjugation reaction, acetylation,
`altered in ESRD. N-acetyltransferase (NAT-2) exhibits
`genetic polymorphisms, with approximately half of the
`African American and Caucasian populations exhibit-
`ing either the rapid or the slow acetylator phenotype.
`The effect of ESRD on acetylator phenotype was
`addressed in the following study (67). First, isoniazid
`and acetylisoniazid pharmacokinetics were determined
`after a single 400 mg oral dose of isoniazid and the
`same protocol repeated after renal transplantation.
`Based on the half-life of isoniazid and using the
`criteria of Reidenberg et al. (68), patients were divided
`into rapid and slow acetylator groups. The pharma-
`cokinetic parameters were compared pre- and post-
`transplantation within each phenotypic group. There
`was a 50% reduction in CLNR in CRF patient in the
`rapid acetylators which was reversed by transplanta-
`tion and there was a threefold reduction in CLNR in
`slow acetylators which was also reversed by transplan-
`tation. This demonstrated that ESRD affected the
`NAT-2 phenotype, reducing the activity of both rapid
`and slow acetylators, and the slow acetylator pheno-
`type was inhibited to a much greater extent.
`These data suggest that drugs which are cleared
`extensively by the liver and exhibit polymorphic meta-
`bolism may be at much higher risk of adverse drug
`reactions in CRF, since the poor metabolizer phenotype
`may be more susceptible to the inhibitory effects of CRF
`on metabolism (67). We have preliminary data from our
`hemodialysis unit to show that ESRD reduces hepatic
`CYP2C9 activity by 50% as measured by the S/R
`warfarin ratio as a phenotypic probe (69). (S-warfarin is
`metabolized exclusively by CYP2C9, while R-warfarin is
`metabolized by multiple pathways.)
`
`Conclusion
`
`There is abundant evidence that nonrenal clearance,
`protein binding, and distribution volume of drugs are
`altered in CRF increasing the risk of adverse drug
`reactions. The majority of the data are in patients with
`ESRD. Even drugs cleared predominantly by the liver
`are significantly affected, especially those which exhibit
`genetic polymorphisms (67,69). Caution should be
`exercised in dosing the drugs in Tables 3 and 4, which
`show significant reductions in nonrenal clearance and
`
`increased bioavailability. Careful titration from the
`lowest dose should be attempted.
`One mechanism of the reduced nonrenal clearance
`appears to be down-regulation of protein expression of
`specific hepatic cytochrome P-450 isozymes. Phase II
`reactions such as glucuronidation and acetylation are
`affected, showing inhibition or induction. This appears
`to be isozyme specific, as well. There is also evidence that,
`at least in the case of propranolol (CYP2D6), there may
`be circulating inhibitors in the serum of ESRD patients
`which may be dialyzable. Otherwise there are scant data
`available concerning the effect of dialysis on these
`changes in nonrenal clearance. More pharmacokinetic
`studies investigating the effect of CRF on nonrenal
`clearance, bioavailability, and plasma protein binding of
`extensively metabolized drugs and mechanisms of these
`phenomena and the effect of dialysis are needed.
`
`Acknowledgment
`
`is a recipient of the
`Albert W. Dreisbach, MD,
`Pharmaceutical Research and Manufacturers of Amer-
`ica Foundation Faculty Development Award in Clinical
`Pharmacology. This work is also supported by the
`GCRC NIH Program Grant #R5M01RR05096-09.
`
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