REVIEW ARTICLES
`
`THE EFFECT OF RENAL FAILURE ON HEPATIC DRUG CLEARANCE
`
`Mark A. Touchette and Richard L. Slaughter
`
`ABSTRACf: It is known that loss of renal function decreases the hepatic
`clearance of some drugs, but the mechanisms by which this occurs are
`unclear. Knowledge of which drugs display reduced hepatic melabolism
`may be important for appropriate dosing of these drugs in uremic
`patients. Although no fum conclusions can be made regarding common
`pharmacokinetic and melabolic characteristics of drugs that display
`decreased hepatic melabolism in renal failure, cenain observations
`deserve consideration. It appears that drugs melabolized by oxidation,
`conjugation, or both may be predisposed to decreased hepatic clearance
`in renal failure. Drugs that undergo oxidation by the P-450nD6 isozyme
`may be more likely to exhibit inhibition wherea<> those melabolized by
`the P-450ffiA4 isozyme may be spared. future studies designed to
`clarify the mechanisms of decreased hepatic clearance in renal failure
`should lake into account the multiplicity of P-450 enzymes for drugs
`that are oxidatively melabolized. The phenomenon of reduced hepatic
`drug clearance in uremia should be considered when evaluating the
`influence of renal failure on drug disposition.
`
`DICP Ann Pharmocorher 1991;25:1214-24.
`
`THE IMPORTANCE OF RENAL FUNCTION in drug clearance is
`well appreciated. As renal function declines, dosage ad(cid:173)
`justment is frequently mandated for those drugs with clear(cid:173)
`ance pathways that are primarily renal. However, the effect
`of renal failure on hepatic clearance processes is not well
`understood. It is known that there is a link between hepatic
`and renal function, as the hepatorenal syndrome is a well(cid:173)
`recognized clinical entity, and many studies have shown
`that loss of renal function can result in decreased hepatic
`clearance of some drugs. This phenomenon may lead to
`greater systemic availability for orally administered drugs
`that exhibit high extraction ratios by decreasing intrinsic
`clearance, or to decreased systemic clearance (Clsy,)for
`drugs with medium or low extraction ratios, depending on
`the magnitude of change in intrinsic clearance and plasma
`free fraction. Knowledge of which drugs display altered
`
`MARK A. TOUCHETTEt Pharm.D .. at the time of writing was a Research Asso·
`ciate and a Fellow in Clinical Phannacokinetic Research. Wayne State University;
`he is now a Clinical Pharmacist in Intensive Care. Henry Ford Hospital. Detroit Ml:
`RICHARD L. SLAUGHTER, M.S .. FCCP. is a Professor and the Chair. Deport·
`ment of Pharmacy Practice. CollegeofPhannacy, Wayne State University, 328 Shap·
`ero Hall. Detroi1. Ml48202. Reprints: Richard L. Siaughler. M.S.
`This work was supported in part by Grant HL 33389·05 from the National Heart,
`Lung and Blood Institute of the National Institutes of Health. and BRSG Grant 2·
`S07RR07051·25 from the National Institutes of Heallh./National Center for Research
`Resources.
`
`This article is approved for continuing education credit.
`
`metabolic clearance can be important for appropriate dos(cid:173)
`ing in renal failure. Matzke and Keane' and Gibson2 have
`addressed this topic in previous reviews. We refer the read(cid:173)
`er to those sources for data concerning the inhibition of
`hepatic clearance of cephalosporins. Data on cefpirarnide,
`an investigational cephalosporin, is included here because
`this information has become available since those reviews
`were published.
`We consider those extensively metabolized drugs that
`show reduced hepatic clearance induced by renal failure,
`comparing their pharmacokinetic and metabolic character(cid:173)
`istics with drugs not so affected. The review focuses pri(cid:173)
`marily on alterations in hepatic clearance. Our purpose is
`to identify the profile of drug substrates that are likely to
`exhibit inhibition of hepatic clearance in renal dysfunction.
`Compounds are categorized as high, low, or unclear ac(cid:173)
`cording to their potential to demonstrate inhibition of hep(cid:173)
`atic metabol.ism in the presence of renal dysfunction.
`
`Background
`We conducted a literature search using MEDLINE (Na(cid:173)
`tional Library of Medicine) for the period of January 1980 to
`July 1990. Some citations before this time period were in(cid:173)
`cluded for background and completeness. Studies were
`identified comparing the disposition of drugs in subjects
`with renal compromise and subjects with normal renal func(cid:173)
`tion. We focused primarily on drugs significantly cleared by
`the liver.
`Because one of our goals was to determine if differ(cid:173)
`ences in hepatic clearance occur between subjects with and
`without renal dysfunction, we include here a brief discus(cid:173)
`sion on basic clearance concepts.
`Intrinsic clearance reflects the maximum metabolic ca(cid:173)
`pability of a clearing organ.3 When a drug is completely
`absorbed after oral administration, intrinsic clearance may
`be estimated from oral clearance (Ct...,):
`Cl = dose~n~
`~n~ AUC~n~
`where AUCora~ is the area under the concentration-versus
`time-curve for an orally administered drug and doseorat is
`the dose of orally administered drug.
`Renal clearance (Cl...,) is the volume of plasma cleared
`of drug per unit of time by the kidneys• and is calculated
`by:
`
`Eq.l
`
`1214 • D!CP, The Annals of Pharmacotherapy • 1991 November, Volume 25
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`Cl = urine flow rate • urine concentration
`Eq. 2
`"'"
`plasma concentration
`CI,,. is equal to the sum of hepatic clearance, CI,. •. and
`any other clearance processes that may take place within
`the body.J When a drug is administered intravenously, c~
`may be calculated from the relationship:
`,.
`=dose;,
`0
`'>y• AUCtv
`
`Eq. 3
`
`where dose;, is the dose of drug given intravenously and
`AUC1, is the area under the concentration-versus-time
`curve for an intravenously administered drug.
`When bioavailability (F), defined as the fraction of a
`given dose of drug that reaches the systemic circulation, is
`known, CI,., can be calculated from the relationship:
`
`Eq.4
`
`Cl = F• dose...,
`AUCon~
`'>rs
`For most compounds, hepatic clearance and CI,.. ac(cid:173)
`count for the great majority of Cl,w In our literature re(cid:173)
`view, we estimated hepatic clearance by subtracting CI,..
`from C~rs when the necessary data were available. That is,
`nonrenal clearance was taken to be an estimation of hepat(cid:173)
`ic clearance. For drugs that are almost exclusively metabo(cid:173)
`lized by the liver, we directly compared clearance values
`regardless of whether or not CI,.. wa~ available.
`For compounds demonstrating a significant first-pass ef(cid:173)
`fect that were only administered orally, For CJ...,.; was taken
`to be an indicator of hepatic metabolic capability. Tilis is be(cid:173)
`cause these drugs tend to demonstrate a significant increase
`in F when intrinsic clearance is decreased. When intrinsic
`clearance changes, drugs that are not appreciably subject to
`tirst-pass clearance (low-extraction drugs) tend not to show
`changes in F of the same magnitude as drugs that do under(cid:173)
`go substantial first-pass clearance (high-extraction drugs).
`Differences in protein binding of drugs between patients
`with renal compromise and healthy volunteers is of con(cid:173)
`cern when comparing clearance values for drugs that are
`highly protein bound and demonstrate low to intermediate
`extraction ratios. These drugs exhibit higher clearance val(cid:173)
`ues as protein binding decreases. Changes in hepatic clear(cid:173)
`ance values between these two patient populations may be
`confounded by differences in protein binding unless these
`differences are ruled out.
`
`Drugs with High Potential for Inhibition
`
`METOCLOPRAMIDE
`Several studies have examined the effects of renal fail(cid:173)
`ure on the pharmacokinetics of various drugs and have re(cid:173)
`vealed that their hepatic metabolism is altered during renal
`failure. Bateman et al. found that the CI,, of metoclo(cid:173)
`pramide hydrochloride in patients with chr~nic renal fail(cid:173)
`ure was approximately 30 percent of that of healthy volun(cid:173)
`t~rs. C~,.. i_n volunteers was 52.5 L/h whereas CJ,., in renal
`failure patients was 16.7 1 L/h. When hepatic clearance
`was estimated by subtracting Cl..,. from CI,.,, it was also
`reduced by approximately the same extent. Hepatic clear(cid:173)
`ance in healthy volunteers was 40.74 L/h; that of renal fail(cid:173)
`ure patients was 15.67 L/h.5 Lehmann et al. reported simi(cid:173)
`lar findings in six adult patients with diminished renal
`function (creatinine clearance [CI.,] 0-10 mL/min) who
`
`were receiving regular hemodialysis. Hepatic clearance in
`the renal failure patients was reported as 0.128 L/kg/h
`whereas that of the normal controls was 0.379 L/kg/h.'
`These studies indicate that hepatic elimination of metoclo(cid:173)
`pramide is impaired in patients with renal dysfunction.
`
`PROPRANOLOL
`In human studies, conflicting results have been reported
`with propranolol hydrochloride. Biancheni et al. reported
`significantly higher F in endstage renal failure patients not
`on regular dialysis (62 percent) and in patients on regular
`dialysis (32 percent) when compared with healthy volun(cid:173)
`teers (19 percent). They also found that a significantly
`higher fraction of the dose was available to the systemic
`circulation in regular dialysis patients during the day of
`dialysis (43 percent) compared with the day after dialysis
`(34 percent).' Wood et al. found no significant difference
`in CI...,, total clearance, or F in patients with stable chronic
`renal failure on hemodialysis or in those not receiving reg(cid:173)
`ular hemodialysis (Cl., 15 ± 2.8 mL/min) when compared
`with age-matched controls. a It may be that in endstage re(cid:173)
`nal failure patients, a dialyzable substance present in the
`systemic circulation is responsible for the increase in F ob(cid:173)
`served in Biancheni's study.
`Animal studies examining the effect of renal failure on
`the pharmacokinetics of propranolol have produced more
`consistent results. Terao and Shen found that although
`serum clearance of S-propranolol was not reduced in rats
`with uranyl nitrate-induced renal failure when compared
`with controls, Cl.,.. was significantly decreased and F was
`significantly increased in the renal failure group. No differ(cid:173)
`ences in protein binding were found.9 Katayama et al. used
`a similar model to investigate the effects of acute renal fail(cid:173)
`ure on the disposition of racemic propranolol. They found
`that C~Y' of propranolol did not differ after intrdvenous ad(cid:173)
`ministration between rats with uranyl nitrate-induced renal
`failure and controls. After oral administration, however, F
`was significantly increased in the renal failure group. Us(cid:173)
`ing liver perfusion studies, these investigators found a sig(cid:173)
`nificant reduction in calculated intrinsic clearance in rats
`with acute renal failure. No differences in protein binding
`or hepatic blood flow were detected.10 Laganiere and Shen
`found no decrease in Cl,1, of S-propranolol in rats with
`acute renal failure induced by bilateral ureter ligation when
`compared with sham-operated controls. However, an in(cid:173)
`crease in the AUCoral corresponding to a significant in(cid:173)
`crease in F was demonstrated 36 hours after ligation.
`Serum protein binding did not differ between the ureter(cid:173)
`ligatt!d and the sham-operated rats.'' The results of these
`animal studies indicate that oral F is increased in patients
`with renal failure because of changes in intrinsic clearance.
`It is likely that hepatic blood flow is unchanged in renal
`failure as the C~,.. of S-propranolol is unaffected.
`
`BETA-BLOCKERS
`
`Bufuralo/. Balant et al. reported a greater than fivefold in(cid:173)
`crease in the circulating concentrations of bufuralol in pa(cid:173)
`tients with Cl,.. values ranging from 5 to 27 mL/min when
`compared with a normal control group. Mean AUC.,.. for
`normal subjects after a 20-mg ordl dose was 500 J.lg•L·1•h;
`that of patients with renal failure was 2800 J.lg•L·1·h. Bu(cid:173)
`furalol is extensively metabolized, subject to first-pass
`
`DICP. TheAn!UllsofPharmacorherapy • 1991 November. Volume25
`
`• 1215
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`metabolism. and is 80-90 percent bound to plasma pro(cid:173)
`teins.u P~ssible differences in binding of bufuralol to plas(cid:173)
`ma protems between the two groups were not studied.
`f!wojilolol. Jeanniot et al. investigated the pharmacoki(cid:173)
`~ocs of butofi.lolol m patients with renal insufficiency and
`m healthy volunteers.U In nonnal subjects. butofilolol is
`predominantly hepatically metabolized and only about 4
`percent of a given dose is excreted unchanged in the urine. ..
`By assuming F to be complete in both groups. a.,. was es(cid:173)
`timated from Eq. 4. The mean clearance value of26.7 L/h
`in the patients with renal failure was approximately 50 per(cid:173)
`cent lower than that of the healthy subjects (57.6 L/h).U
`This suggests a reduction in CJ.,,: however. these values
`must be interpreted with caution because F was assumed to
`be complete in both groups. Also, the possible contribution
`of changes in plasma protein binding to the observed differ(cid:173)
`ence in clear.mce values was not determined.
`OJ.prenolol. The consequences of renal failure on the
`phannacok.inetics of oxprenolol have been investigated by
`Dayer et a!. Patients with renal failure requiring hemodialysis
`were compared with a group of healthy subjects.u Ox(cid:173)
`prenolol is rapidly eliminated by hepatic metabolism, and
`I~ than five percent of a dose is excreted unchanged in the
`unne." The mean AUC.,., was 681 ng•mL-1/h in the renal
`failure patients, a value significantly higher than that of 369
`ngoffiL·11h reponed in normal volunteers. ~ible differences
`in F and protein binding were not measured.u These studies
`demonstrate a high potential for inhibition of the nonrenal
`clearance of lipophilic beta-blockers that have high intrinsic
`clearance values and are primarily eliminated by oxidative
`bioo'ansfOfTllalion in patients with renal dysfunction.
`
`reduced in this study, its half-life (11/2) was shorter in there(cid:173)
`nal failure group resulting from a significantly decreased
`volume of distribution (V.)." We cooclude that renal failure
`has significant effects on the disposition of encainide."
`
`VERAPAMIL
`
`Storstein et al. studied the pharmacokinetics of vera(cid:173)
`pamil hydrochloride in patients with advanced renal failure
`(aged 33-70 y) and nonnal volunteers (aged 50-65 y).•
`Verapamil is a high-clearance compound with negligible
`Cl,...u It has been reported that binding of verapamil to
`plasma proteins does not differ between nonnal subjects
`and patients with renal failure}l The mean nonrenal clear(cid:173)
`ance value in the uremic patients was 5.33 mL·min-1•k.g-'. a
`value significantly lower than the mean value of 11 .7
`mL•min·'•kg ' reported in the normal control group.•
`Mooy et al. studied the pharmacokinetics of ve.rapamil in
`patients with cndstage chronic renal failure and in nonnal
`subjects. After administration of a single 3-mg intravenous
`dose of verapamil. there was no difference in clearance val(cid:173)
`ues between the two groups. After administration of a sin(cid:173)
`gle 80-mg_oral dose to both groups, the mean AUC.,., in
`the renal failure group was 17.8 ± 1.09).1g•mL-1•min; that in
`~e noT!flal subJec.~ was 10.5 ± 4.82 ).1g•mL-1•min. Large
`mterpallent vanab1hty and small subject numbers resulted
`in statistical significance not being achieved.u Although
`these data suggest the hepatic cleanmce of verapamiJ is de(cid:173)
`creased ~n renal failure. furthe_r study is needed to clarify
`the spec1fic effects of renal failure on the hepatic metab(cid:173)
`olism of verapamil.
`
`F. CAJNIO£
`
`NIMODrPrNE
`
`Bergstrand et al. compared the disposition of encainide
`hydrochloride in patients with renal failure (CI.. 10-38
`ml../min)11 to that in nonnal volunteers from a study by
`Wang et al.'" ln nonnal volunteers phenotyped as extensive
`metabolizers, encainide is almost completely metabolized
`to _G_-demethylen.cainide and 3-methoxy-0-demethylen(cid:173)
`camtde." After smgle-dose administration of both intra(cid:173)
`venous and oral encainide, Bergstr.md et al. found that both
`Cl .... and Ct.i.' w.ere decreased.in the renal failure group.
`The mean C ..... m the renal fatlure group was 2.7 L/min
`whereas thnt in the normal subjects was 12.4 L/min. The
`mean Cl,1, value in the renal failure group was I .I L/min
`~ ~t ~n the nOf!ll~ subjects was 1:8 L/min. Plasma pro(cid:173)
`tem bindmg was s1gruficantly lower m the normal subjects
`(70 percent) than in the renal failure patients (81 percent).
`Some. but not all. of the d1fferences found in Ct_ and CJ...
`~ues may have been a result of differences in protein bind(cid:173)
`mg. as the unbound fraction of drug was higher in the nor(cid:173)
`mal volunteers. F was higher in the renal failure patients
`( 45 percent) when compared with the normal subjects (26
`percent), but the difference did not reach statistical signifi(cid:173)
`cance. After the administration of a single intravenous dose
`and repeated oral doses of encainide in the same groups,
`CJ.,., was still significantly lower in the renal failure pa(cid:173)
`~enf:S. but in~venou~ cl~ce (Cl,.,J was not. F was not
`SlgJU.ficantly dtfferent m e1ther group after single- or repeat(cid:173)
`ed-dose administration. Although encainide clearance wa~
`
`EDTI'OR'S 1'1011!: AJ ofO«<mb<r 16. 1991, encouudets no looJ!<r o...table by~
`:'~.:...~US. th,. ICIIon- W.m by Bnstol Myc,. Sqwbb. See oho page 1294
`
`Kirch et al. compared the pharmacokinetics of nirnodi(cid:173)
`pine in pati~ts with renal dysfunction (aged 39-77 y, a.,.
`3-63 mL/mm} with that of healthy volunteers (aged 18-
`34 y}.JA Nimodipine is extensively metabolized with less
`than ~ne percent of a dose .being recovered unchanged in
`the unnc.u The nonnal subjCCts were given nimodipine 40
`m~ orally ~ .times daily fo~ one week, and the subjects
`With renal1mpcurment were g1ven 30 mg three times daily
`h was
`for one week. After the last dose, the mean AUC0
`•
`72
`significantly higher in the renal failure group (541.5 ng•mL·
`1•h} than in the nonnal subjects (74.65 ng•mL·•·h). The
`me~ elimi~ation tl/2 was also significantly greater in the
`subjects w1th renal dysfunction (22.23 h) than in the
`healthy volunteers (2.77 h}.JA These data suggest high po(cid:173)
`tential for inhibition of hepatic metabolism of nirnodipine
`in renal dysfunction.
`
`CAPTOPRJL
`~hin et al. compared.the elimination kinetics of cap(cid:173)
`topnl m four groups of panents with varying degrees of re(cid:173)
`nal dysfunct~on; group I, mild renal dysfunction (CI.,.
`53-73 mLimt~); group 2, moderate renal impairment (CI..
`23-4 1 mLI!f!m); group 3, severe renal impairment (CI,.
`4 - 14 mUmin): group 4, patients maintained on hemodial(cid:173)
`ysis (CJ... < I ml../min) who were studied during the interdi(cid:173)
`alyti~ period.» ln patients with nonnal renal function, ap(cid:173)
`proximately 40-50 percent of a dose is excreted un(cid:173)
`changed in the urine, with the remaining drug being rapidly
`metabolized to captopril-cysteine disulfide and the disul(cid:173)
`fide dimcr of captopril.11 In this study F was assumed to be
`
`1216 • DICP. TlteAnll(l/sofPiu:mnacotherapy • 1991 November, Volume25
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`
`equal to the fraction of a dose of '"C-captopril that was re(cid:173)
`covered in the urine over a 96- to 120-hour period. Mean
`nonrenal clearance values were as follows: group I, 3.0
`mL/min/kg; group 2, 2.8 mL/min/kg; group 3, 1.5 mL/
`min/kg, and group 4, 1.6 mL/min/kg. These values were
`significantly lower in groups 3 and 4 when compared with
`groups I or 2.'6 Cl,,, (blood) was calculated from Eq. 4.
`Values obtained by this method for the patients in group 4
`must be interpreted with caution, however, because the F
`in this group was determined to be significantly lower than
`in the other groups because of considerably reduced uri(cid:173)
`nary excretion of the radiolabeled drug. The nonrenal
`clearance of captopril appears to be reduced in severe renal
`impairment only.
`
`NORTRIPTYLINE
`
`Dawling et al. compared the pharmacokinetics of nor(cid:173)
`triptyline hydrochloride in patients with chronic renal fail(cid:173)
`ure (aged 18-73 y) with those of normal subjects. Eight of
`the 20 patients in the renal failure group required hemo(cid:173)
`dialysis. The remaining 12 patients had Cl.,. rdiiging from 4
`to 53 mL/min and were not on chronic hemodialysis.28 ln
`normal subjects nortriptyline is extensively metabolized by
`oxidation and conjugation and less than two percent of an
`administered dose is recovered unchanged in the urine.19 It
`is highly bound to plasma proteins (94 percent)JOand F af(cid:173)
`ter oral administration has been reported to be 56-70 per(cid:173)
`cent.31 When results from Dawling's study were compared
`with results from a study conducted by Alexanderson and
`Borga (Aiexanderson and Borga's study group comprised
`five pairs of monozygotic and six pairs of dizygotic twins
`aged 47-53 y),19 no significant differences in clearance
`values could be detected. However, when compared with a
`group of normal volunteers (aged 26 ± 6 y),28 a significant(cid:173)
`ly lower median CJ..., was shown in the renal failure group
`(32.1 L/h, n=20) than in the healthy volunteers (51.4 L/h,
`n=30). No measurements of protein binding were ob(cid:173)
`tained, however.
`
`HepaJic Drug Clearance
`
`of a single intravenous dose of chlorazepate dipotassium,
`the investigators found no difference between the two
`groups in Cl,1., of desmethyldiazepam, but the unbound
`fraction of desmethyldiazepam in the plasma was signifi(cid:173)
`cantly higher in the renal failure patients (1 !.1 percent)
`than in the control group (4.1 percent). When the clearance
`of free drug was calculated, a significantly lower value
`was obtained in the patients with renal failure (2.5
`mL/min/kg) than in the control group (6.9 mL/min/kg)_ls
`These data suggest that the clearance of free desmethyl(cid:173)
`diazepam is significantly lower in patients with renal fail(cid:173)
`ure than in normal subjects
`
`ERYTHROMYCIN
`
`Kanfer et al. investigated the changes in erythromycin
`pharmacokinetics induced by renal failure.37 Erythromycin
`ethylsuccinate is partly metabolized by N-demethylation,
`but is primarily excreted unchanged in the bile.38 Three
`groups of patients were evaluated. Group I consisted of pa(cid:173)
`tients 41- 53 years of age with advanced renal failure stud(cid:173)
`ied on an interdialytic day. Group 2 consisted of patients
`18- 6 I years of age with advanced renal failure studied im(cid:173)
`mediately after the end of a hemodialysis session. Group 3,
`the control group, comprised healthy volunteers 22-41
`years of age. After oral administration of erythromycin
`ethylsuccinate I g, the investigators found that the AUC.,..1
`values were significantly higher in both renal failure groups
`when compared with the control group. The AUC...., values
`obtained were: group 1, 20.1 mg•L·1•h; group 2, 20.9 mg•l:!
`•h; and group 3, 4.7 mg•L·'•h. Because t 1k was not signifi(cid:173)
`cantly different among any of the groups, the increased
`AUCo,., values found in the renal failure groups may have
`resulted from concurrent decreases in C~,. and Vd or an in(cid:173)
`crease in FY Because the Vd of erythromycin has been
`shown to be increased in renal failure,39 the most likely ex(cid:173)
`planation for the increa<;e in AUC...., values in the renal fail(cid:173)
`ure patients in this study is an increase in F, pemaps because
`of decreased hepatic uptake of the drug.
`
`PROPOXYPHENE
`
`ZIOOVUDINE
`
`Gibson et al. studied the pharmacokinetics of propox(cid:173)
`yphene hydrochloride in anephric patients (aged 23-55 y)
`and in healthy volunteers (aged 29-36 y).31 In normal
`subjects, propoxyphene is primarily metabolized in the
`liver by N-demethylation.33 After administration of a sin(cid:173)
`gle oral dose, the values of AUC0.11 " for propoxyphene
`were significantly higher in the anephric patients (808
`ng•mL·1•h) than in the normal subjects (3R3 ng•ml:1•h)_3l
`Plasma protein binding of propoxyphene has been shown
`to be similar in anephric and in healthy patients.34 If com(cid:173)
`plete absorption of propoxyphene is assumed, the increase
`in AUC observed in anephric patients may be attributed to
`decreased presystemic biotransformation of the com(cid:173)
`pound.
`
`DESMETHYLDIAZEPAM
`
`Ochs et aL compared the pharmacokinetics of des(cid:173)
`methyldiazepam in patients with renal failure requiring
`maintenance hemodialysis with that of age-, weight-, and
`sex-matched controls.35 Desmethyldiazepam is virtually
`completely metabolized and its absolute F has been report(cid:173)
`ed to be approximately 99 percent.36 After administration
`
`Singlas et al. studied the disposition of zidovudine in pa(cid:173)
`tients with renal failure (CI.,. 6-31 mL/rnin) and in healthy
`volunteers. Zidovudine is eliminated primarily by glu(cid:173)
`curonidation in the liver (75 percent) with the remaining
`25 percent of drug being eliminated unchanged by the kid(cid:173)
`ney. F of zidovudine is approximately 60-70 percent. The
`authors found that after administration of a single 200-mg
`oral dose to both groups, mean AUC""" values were signif(cid:173)
`icantly higher in the renal failure group (11.7 J..lmol•L·1•h)
`than in the control population (5.2 J..lmol•L-•·h).46 At least
`some of the increase in the mean AUC..-.~ values of there(cid:173)
`nal failure group is undoubtedly a result of decreased Cl..,
`of unchanged drug. However, the magnitude of the in(cid:173)
`crease in mean AUC0 , .1 cannot be fully explained by the
`decreased Cl..., •. If the liver is the only site of zidovudine
`metabolism, it may be concluded that hepatic clearance of
`this drug is decreased in renal failure.
`
`Drugs with Low Potentia/for lnhibiJion
`Some studies that have investigated the effects of renal
`impairment on particular drugs have shown no significant
`effect of renal failure on nonrenal clearance.
`
`DICP, TheAnna/sofPharmacotherapy
`
`• 1991 November, Volume25
`
`• 1217
`
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`aop.sagepub.com
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`Boehringer Ex. 2017
`Mylan v. Boehringer Ingelheim
`IPR2016-01565
`Page 4
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`

`
`METOPROLOL
`Metoprolol tartrate pharmacolcinetics have been studied
`in patients with renal failure (aged 27-49 y, Cl, 5- 55
`mL/min) and in nonnal controls (aged 22-28 y) by Jordo
`et al.41 In healthy subjects, metoprolol is primarily metabo(cid:173)
`~ in the liver by ox.idative deamination, 0-dealk:ylation
`w1th subsequent oxidation. and aliphatic hydroxylation. It
`undergoes first-pass metabolism and approximately 50
`percent of a given dose reaches the systemic circulation. •L,<l
`After admin}stration of 20 mg intravenously followed by
`50 mg as a smgle oral dose (under steady-state conditions),
`Cl.,.. AUC.,.... and F were not found to be significantly dif(cid:173)
`ferent between the two groups."
`
`TOCAINJDE
`B~~n et al. in~e~tigated the pharmacokinetics of orally
`administered tocaarude hydrochloride in patients with renal
`dysfunction (Clrr II ± 7.8 mL/min/1.73 m2) and in a nor(cid:173)
`mal ~ontrol group.0 In healthy volunteers tocainide is ap(cid:173)
`proxamately 40 percent excreted unchanged in the urine,
`and is metabolized in the liver primarily by carboxylation
`and subsc:<~uent conjugation. II is minimally bound to plas(cid:173)
`ma protems and the absolute F of orally administered to(cid:173)
`cain ide is about 100 percent. .. When Cl,,, is calculated
`~~ Eq. 4 where F is assumed to be 1.0 in both groups, a
`s1gnaficantly lower value is obtained in the group of pa(cid:173)
`tients with renal failure because of decreased Cl,..., of the
`drug, as would be expected. However, when nonrenal
`clearance is approximated, no significant difference is
`found.
`
`UDOCAfNE
`Thomson et al. studied the pharmacokinetics of intra(cid:173)
`v~nously ada:ninistered lidocaine hydrochloride in patients
`WI~ renal f~lure_ (aged 24- 57 y) who were receiving peri(cid:173)
`odiC hemodaalysas.45 In nonnal subjects, F of an orally ad(cid:173)
`ministered dose of lidocaine is approximately 35 percent.
`Li~ocaine is primarily metabolized by the liver by de-ethy(cid:173)
`lauon followed by cleavage of an amide bond. Less than
`ten percent of a parenterally administered dose is excreted
`unchanged in the urine. The authors found that CI.,, of this
`drug was not appreciably different from that obtained in
`healthy volunteers." ln a group of uremic patients on
`chronic hemodialysis. CoUinsworth et al. also reported C~
`values sim_ilar to those in nonuremic subjects.47 lt ap~
`that hepauc clearance of lidocaine is not significantly
`changed in renal dysfunction.
`
`NTTRENDtPfNE
`Aranoff compared the pharmacokinetics of nitreodipine
`in p~tien~ with renal dysfunction (CI,. 11-45 ml.Jrnin),
`anunc patients, and in healthy volunteers ... It has been re(cid:173)
`ported elsewhere that plasma protein binding of nitrendi(cid:173)
`pine does not differ appreciably between healthy volun(cid:173)
`teers (95.8 percent) and patients with tenninal renal failure
`(95.7 percent) ... In nonnal subjects nitrendipine is almost
`completely metabolized in the liver by dehydrogenation to
`a pyridine analog. cleavage of the ester groups by hydroly(cid:173)
`~is, _or oxidati~n and hydroxylation of the methyl groups. It
`1s hi~y protem bound (approximately 98 percent) and ap(cid:173)
`proxamately 30 percent of an orally administered dose
`reaches the systemic circulation. 50 When Ci...J is calculated
`
`from data presented in Aranoff's study, no simificant dif(cid:173)
`ference is obtained among any of the groups.<~ .....
`Bortel et al. studied the disposition of nitrendipine in pa(cid:173)
`tients with terminal renal failure and in nonnal controls.
`(Uter a~tration of a single 40-mg oral dose, oo signif(cid:173)
`ICant dafferences were found in time to maximum plasma
`concentration (t_.), the max.imum plasma concentration
`(C_.), or the tenninal elimination t1J2 (Stitz). After intra(cid:173)
`venous infusion of 15 mg. no significant differences were
`found in llt1/2. AU~. clearance, or Yd. After administration
`of 20 mg orally twice daily for five days no significant
`differences were found in trough conce~tions, C,.... or
`r,... AUC- values were not reported for the 40-mg or 20-
`mg dose regimens . .,
`. Afl!<erman_n et al. ~tudied the elimination of nitrendipine
`tn pauents With artcnal hypertension and differing degrees
`of renal function (median Ct.. 27. 1 mL/min) and in control
`subjects with arterial hypertension. In contrast to the two
`previous studies, these authors reported that the mean
`A UCo.1• and elimination t'/2 of nitrendipine were signifi(cid:173)
`cantly highe~ in the p~ti~nts with renal failure. 51 Although
`most of the hterature mdicate that there is low potential for
`inhibition of hepatic metabolism of nitrendipine in renal
`failure, further study is needed to clarify this issue.
`
`NIFD>IPINE
`The pharmacokinetics of nifedipine have been com(cid:173)
`pared in patients with tenninal renal failure and in healthy
`~OL':Iflteen. by Bortel et al.Sl In normal subjects, nifedipine
`1s VIrtually completely metabolized to inactive metabolites
`by oxi~ion.u The F of orally administered nifedipine is
`approximately 50 percent. so After an intrnvenous dose of
`4.4 mg. patients with renal failure actually had significant(cid:173)
`ly lower mean AUC,. values than did the healthy volun(cid:173)
`teers. Significantly lower AUC- values were obtained in
`the renal failure group after single-dose oral administration
`of 10 mg to both groups. Protein binding was not signifi(cid:173)
`cantly different between the groups.'2 Although the reason
`for lowe~ ":lean AUC1• values in the renal failure group is
`unclear, II IS apparent that the hepatic metabolism of ni(cid:173)
`fedipinc is not decreased in renal failure if complete ab(cid:173)
`sorption is assumed in both groups.
`
`ISRAOIPINE
`. Chandler et al. compared the effects of renal dysfunc(cid:173)
`uon on the pharmacokinetics of isradipine in nonnal con(cid:173)
`trols (n= 16) and i