`Printed in Denmark Ail rights reserved
`Munksgaurd Copenhagen
`
`Copyright 0 European Association
`for the Study of the Liver 1997
`Journal of Hepatology
`ISSN 0168-8278
`
`Effect of liver cirrhosis on the systemic availability of naltrexone in
`humans
`
`Marco Bertolotti’,2, Anna Ferrari’, Giovanni Vitale’, Marina Stefani’, Tommaso Trenti’, Paola Loria2,
`Francesca Carubbi2, Nicola Carulli2 and Emilio Sternieri’
`‘Servizio di Tossicoiogia e Farmacologia Clinica and ‘Divisione di Medicina Interna III, Dipartimento di Medicina Interna, Universitci di Modena,
`Modena. Italy
`
`Background/Aims: Naltrexone
`is a competitive opiate
`antagonist with high hepatic extraction. It is used for
`detoxification
`treatment for heroin addicts and has
`been proposed as a possible treatment of pruritus in
`cholestasis. Such patients are likely to have impaired
`liver function, underscoring the need to understand
`the pharmacokinetic behavior of naltrexone
`in liver
`disease. These studies were undertaken to evaluate the
`effect of liver cirrhosis on the plasma time-course of
`naltrexone.
`Methods: A total of 18 patients were investigated:
`seven migraine patients with normal liver function re-
`garded as controls and 11 patients with liver cirrhosis
`(six with decompensated disease and five with pre-
`served liver function). A bolus of 100 mg of nal-
`trexone was administered orally in the morning, after
`an overnight fast. Blood samples were taken in basal
`conditions and at fixed intervals, up to 24 h after ad-
`ministration. Serum levels of naltrexone and of its
`major active metabolite, 6/3-naltrexol, were assayed
`by reversed-phase HPLC analysis.
`Results: In control subjects, circulating concentrations
`of naltrexone were always much lower than those of
`6/?-naltrexol
`(area under
`the curve: naltrexone,
`200&97 ng/mlX 24 h; 6/3-naltrexol, 24672730
`ngl
`
`In severe cirrhosis serum levels of
`ml x 24 h, ~~0.01).
`6/3-naltrexol increased more slowly, so that circulating
`levels of naltrexone during the first 24 h after drug
`intake were higher than those of 6P-naltrexol(6b-nal-
`trexobnaltrexone
`ratio at 2 h: controls, 10.91&4.80;
`cirrhosis, 0.39+0.18, ~~0.01). The area under the
`curve for naltrexone (16102629 ng/mlX24 h) was sig-
`nificantly greater than in controls, whereas that for
`6B-naltrexol
`(20212955
`ng/mlX24 h) was not sig-
`nificantly different. Patients with compensated cir-
`rhosis showed an intermediate pattern. No differences
`in elimination half-life of the two drugs were detected
`among the groups.
`Conclusions: Our data suggest the occurrence of im-
`portant changes in the systemic availability of nal-
`trexone and 6/l-naltrexol in liver cirrhosis; such alter-
`ations are consistent with lesser reduction of nal-
`trexone to 6B_naltrexol and appear to be related to
`the severity of liver disease. This must be considered
`when administering naltrexone
`in conditions of liver
`insufficiency.
`
`Key words: Liver cirrhosis; Naltrexone; Pharmacoki-
`netics; Systemic availability; 6/?-naltrexol.
`
`N ALTREXONE (N-cyclopropyl-methyl-noroxymor-
`
`phone) is a potent competitive antagonist of opi-
`ates at the receptor
`level (1,2). When administered
`orally to human subjects, naltrexone can prevent
`the
`pharmacological
`effects of active doses of heroin for
`
`Received 20 December 1996; revised 3 April; accepted 8 April 1997
`Correspondence: Marco Bertolotti, MD, Divisione di
`Medicina III, Dipartimento di Medicina Interna, Poli-
`clinico, Via de1 Pozzo 71, 41100 Modena, Italy.
`Tel: 39 (59) 424939. Fax: 39 (59) 363114.
`
`prop-
`48-72 h (3). Because of these pharmacological
`erties, naltrexone has been proposed for the treatment
`of heroin addicts,
`to prevent relapse. Its efficacy has
`been documented
`in clinical studies (1,2,4) and at the
`present
`time naltrexone
`is registered
`in a number of
`European countries,
`including Italy, for this indication.
`Very recent evidence has suggested its use in former
`alcohol addicts as well (5).
`are
`The pharmacokinetic
`properties of naltrexone
`not completely understood
`(6); the drug is well ab-
`sorbed by the gastrointestinal
`tract and is efficiently
`
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`M. Bertolotti et al.
`
`extracted by the liver (7) where it is converted by enzy-
`matic reduction
`to 6P-naltrexol and to other minor de-
`rivatives (2,8). Both the parent drug and its metabolites
`are conjugated with glucuronic acid and then excreted,
`mainly by the kidney and to a lesser extent via the
`biliary
`route. The elimination half-life has been re-
`ported
`to be lo-12 h, for both naltrexone and 6p-nal-
`trexol (9); although conflicting
`results have been re-
`ported
`in the literature
`(2,8), these kinetic properties
`seem to justify a single daily administration
`of the
`drug. Due to the extensive metabolism of naltrexone,
`it is believed that most of the pharmacological
`effects
`still present 12-24 h after drug administration
`are ac-
`counted
`for by active metabolites,
`the principal one
`being 6P-naltrexol (2).
`role played by the liver and
`Despite
`the important
`by the kidney in naltrexone disposition, very little in-
`formation
`is presently available on the effects of hep-
`atic and kidney disease on naltrexone pharmacokinet-
`its. The issue of liver function is particularly
`important
`when we consider that most candidates
`for naltrexone
`treatment are likely to be, or to become, chronic liver
`disease patients. Theoretically,
`in this condition, alter-
`ations in the systemic availability of naltrexone and/or
`of its metabolites might underlie increased susceptibil-
`ity to its potential side effects, even if the drug, so far,
`has proven to be well tolerated
`in most clinical settings.
`Furthermore,
`recent evidence has suggested the in-
`volvement of opiate receptors
`in the pathogenesis of
`pruritus
`in some forms of chronic cholestasis, such as
`primary biliary cirrhosis (10,l l), where the utilization
`of opiate antagonists has been proposed as a sympto-
`matic treatment
`(12). Compared
`to naloxone,
`the most
`extensively studied antagonist, naltrexone would pres-
`ent the advantage of longer half-life and, most of all,
`the possibility of oral administration. Preliminary evi-
`dence has encouraged
`this approach
`(13).
`
`the ef-
`to investigate more systematically
`In order
`fects of altered liver function on naltrexone pharmaco-
`kinetics, we studied a group of patients with a clinical
`diagnosis of cirrhosis of the liver. The main pharmaco-
`kinetic parameters of naltrexone and 6P-naltrexol were
`analyzed after an oral bolus of naltrexone.
`
`Materials and Methods
`Patients and design of the study
`In total, 18 patients were investigated. Seven of them
`(two males, five females, age range 42-73) were mi-
`graine patients with normal
`liver function, as assessed
`by clinical and laboratory
`evaluation,
`and were re-
`garded as controls. Eleven patients had a well-estab-
`lished diagnosis of liver cirrhosis (see Table 1 for clin-
`ical relevant data). Six of them (patients 6-l 1) had de-
`compensated
`liver disease and were Child-Pugh class C
`(14). The remaining five (patients
`l-5) had a milder,
`more compensated
`form of the disease (Child-Pugh
`class A or B). Patients were investigated as inpatients
`or as day-hospital patients in the wards of the Depart-
`ment of Internal Medicine of the University of Mod-
`ena. All subjects gave their informed consent
`to the
`design of the study, which was conducted according
`to
`the Declaration of Helsinki.
`In the morning, after an overnight fast, patients re-
`ceived an oral bolus of 100 mg of naltrexone, as two
`50-mg capsules
`(ANTAXONE@, Zambon Pharma-
`ceuticals, Milan, Italy). Blood samples were collected
`in heparin-free
`tubes in basal conditions
`just before
`drug administration,
`and subsequently at fixed inter-
`vals (20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24
`h) after naltrexone. The occurrence of side effects was
`recorded. The morning
`after
`the beginning of the
`study, a serum sample was taken for analysis of liver
`enzymes.
`A subgroup of patients
`
`(four controls,
`
`two with
`
`TABLE 1
`
`Relevant clinical data of patients with cirrhosis
`
`studied
`
`Patient
`
`Age
`
`Sex
`
`29
`59
`61
`65
`41
`40
`62
`64
`52
`70
`56
`
`M
`F
`F
`F
`M
`M
`F
`M
`M
`M
`M
`
`9
`10
`11
`
`AST
`
`mum1
`
`78
`62
`69
`61
`144
`57
`123
`158
`104
`60
`32
`
`ALT
`
`106
`80
`48
`68
`187
`34
`52
`170
`59
`42
`18
`
`PChe
`U/ml
`
`Child-Pugh
`score
`
`Etiology of
`cirrhosis
`
`5.0
`6.8
`4.0
`5.1
`5.3
`2.4
`1.4
`2.0
`1.5
`2.9
`3.2
`
`6
`6
`7
`8
`10
`10
`10
`11
`11
`12
`
`HBV
`HCV
`HCV
`HCV
`HBV
`Alcoholic
`HCV
`HCV
`HCV
`Alcoholic
`Unknown
`
`AST=aspartate
`
`aminotransferase.
`
`ALT=alanine
`
`aminotransferase.
`
`PChe=pseudocholinesterase.
`
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`cirrhosis)
`compensated and three with decompensated
`also underwent
`analysis of caffeine kinetics, as an
`index of hepatic drug-metabolizing
`capacity. Subjects
`were given, together with the naltrexone bolus, 100 mg
`of caffeine; blood was taken at fixed intervals, as de-
`scribed above, and an aliquot of serum was used for
`the determination of caffeine levels, assayed by enzyme
`multiplied
`immunoassay
`technique
`(EMIT Bracco-
`Syva Chemicals, Milan, Italy).
`
`and 6/G
`
`of naltrexone
`
`Analysis of serum concentrations
`naItrex0~
`tubes
`Blood was collected in polyethylene heparin-free
`and serum was stored at -20°C until assayed by re-
`verse-phase HPLC, according
`to Zuccaro et al. (15)
`with modifications. After solid-phase extraction using
`Bond Elut C-18 cartridges (Analytichem
`International,
`Harbor City, CA, USA), drug assays were performed
`with a Beckman System Gold high-performance
`liquid
`chromatograph
`equipped with a diode array detector
`module 168, set at 202 nm (Beckman Instruments,
`Inc.,
`San Ramon, CA, USA). A reversed-phase C-18 25
`cmX4.6 mm Hypersil column (Labservice Analytical,
`Bologna, Italy) packed with 5 pm ODS was used.
`18%
`The mobile phase, composed of acetonitrile
`and 20 mmol/l KH2P04 82% with 0.015% (v/v) triethy-
`lamine, pH 3, was pumped at a rate of 1 ml/min.
`Naloxone
`(the internal standard), naltrexone and 6p-
`naltrexol were used as standards.
`Standards
`and
`samples were quantitated
`according
`to the analytel
`naloxone
`ratio in a calibration curve. The sensitivity
`limit of the assay was 10 @ml for both drugs. Within-
`day and between-day precision measurements gave a
`coefficient of variation of 4.8% and 7.1%, respectively,
`for naltrexone
`and 4.2% and 6.9% for 6/3-naltrexol
`(mean of the values obtained at drug concentrations of
`10, 100 and 500 ng/ml).
`
`evaluation
`Analysis of the data and statistical
`Maximal drug concentration
`(Cmax) and time to peak
`drug concentration
`(Tmax) were determined by direct
`analysis of the data. The area under the curve (AUC)
`was determined by the trapezoidal
`rule, restricted
`to
`the time interval of experimental
`samples. The elimin-
`ation half-life (T/2) of naltrexone and 6,!$naltrexol was
`calculated by non-linear
`regression analysis using a
`two-compartment,
`three-exponential model. The elim-
`ination half-life of caffeine was calculated by a one-
`compartment monoexponential model on
`the dec-
`remental portion of the time-course curve.
`Data were expressed as the mean+SD. The signifi-
`cance of the differences between groups was investi-
`gated by Student’s t-test for independent data. When
`
`nglml
`
`350
`
`100 -
`
`50 -
`r,
`
`0
`0
`
`-
`
`- __
`
`7_r_-_L_-L__-_-__T
`10
`5
`15
`Time after drug admlni~ration fh)
`COMPENSATED CIRRHOTIC3
`In = 51
`
`_____
`
`_f _...__..q
`20
`
`,OOfl
`
`200
`
`150
`
`100
`
`50
`
`0
`0
`
`6
`
`15
`10
`Time after drug administration Ih)
`DECOMPENSATED CIRRHOTICS (II = 6)
`
`20
`
`nglml
`
`200
`
`,
`
`Naltrexone bioavailability in cirrhosis
`
`CONTROL SUBJECTS (n = 7)
`
`-- N&rEzIgl*
`
`+ 6s-&tr*1ol
`
`25
`
`25
`
`20
`
`25
`
`0
`
`6
`
`10
`15
`(h)
`Time after drug adm~~trati~
`(broken
`Fig. 1. Time course of plasma
`levels of naltrexone
`line) and 6@altrexol
`(continuous
`line), after oral adminis-
`tration of 100 mg of naltrexone
`in seven subjects with nor-
`in five patients with com-
`mal liver function
`(upper panel),
`pensated
`(Child-Pugh
`class A or B) cirrhosis
`(middle
`panel) and in six with decompensated
`(Child-Pugh class C)
`cirrhosis
`(lower panel). Data represent mean values and
`SD.
`
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`
`**mm concentrations
`
`(nghll
`
`Maximal
`/
`
`I
`
`0
`
`CONTROLS
`I71
`
`COMP. CIRRHOTICS
`(5)
`
`CIRRHOTICS
`(61
`
`m
`Naitrexone
`6R-Naltrexol
`m
`of nal-
`serum concentration
`Fig. 2. Maximal
`(Cmax)
`trexone and 6p-naltrexol
`in control subjects, patients with
`compensated and decompensated cirrhosis after oral admin-
`istration of 100 mg of naltrexone. Data indicate mean value
`and SD. * p<O.Ol vs controls, Student’s
`t-test for unpaired
`data.
`
`AUC
`
`inglml
`
`l hl
`
`3500,
`
`3000 t
`
`2500
`
`1
`
`T
`
`I
`
`500
`
`0
`
`CONTROLS
`(71
`
`COMP. CIRRHOTICS
`(5)
`
`CIRRHOTICS
`161
`
`m Naltrexone
`m 66.Naltrexol
`Fig. 3. Area under the curve (A UC) of naltrexone and 6p-
`naltrexol
`in control subjects, andpatients with compensated
`cirrhosis and decompensated cirrhosis after oral administra-
`tion of 100 mg of naltrexone. Data
`indicate mean value
`and SD. * p<O.Ol vs controls, Student’s
`t-test for unpaired
`data.
`
`linear correlation and regression analyses
`appropriate,
`were performed using the least-squares method. A level
`of p<O.O5 was considered
`to be statistically significant.
`
`Results
`Figure 1 shows plasma time courses of naltrexone and
`6P-naltrexol
`in control subjects, and in patients with
`compensated
`(Child A-B) cirrhosis and decompensated
`(Child C) cirrhosis.
`In control
`subjects circulating
`levels of naltrexone were almost undetectable
`soon
`after drug administration, whereas the concentrations
`of 6/?-naltrexol sharply
`increased over the first l-2 h;
`
`508
`
`levels were consistently much higher
`6/Gnaltrexol
`the period of observation.
`In contrast
`in
`throughout
`patients with decompensated cirrhosis, circulating con-
`centrations of naltrexone were markedly higher, par-
`ticularly at the earlier time points after drug adminis-
`tration; furthermore,
`the rise of 6P-naltrexol was much
`slower, so that plasma levels of naltrexone over the first
`24 h were higher than those of 6P-naltrexol. Patients
`with compensated cirrhosis displayed an intermediate
`pattern, with naltrexone
`and 6/?-naltrexol
`levels of
`nearly the same order of magnitude at the earlier time
`points.
`To stress more clearly the different pharmacokinetic
`behavior, Fig. 2 illustrates the values of Cmax and Fig.
`3 shows the values of the AUC in the groups investi-
`gated.
`and 6/?-naltrexol
`of naltrexone
`Other parameters
`in the different
`pharmacokinetics were investigated
`groups of patients. The value of Tmax for 6/?-naltrexol
`was significantly higher
`in patients with decompen-
`sated cirrhosis
`(260% 143 min) compared
`to controls
`(432 14 min, ~~0.02) and those with compensated cir-
`rhosis (55?21 min, p<O.O2), consistently with a delay
`in the metabolism of naltrexone; differences with re-
`gard to naltrexone Tmax were not statistically signifi-
`cant (data not shown). No significant differences in the
`elimination half-life of parent drug and metabolite
`could be detected between different
`groups
`(nal-
`trexone: controls, 14? 12 h; compensated
`cirrhosis,
`17 +9 h; decompensated cirrhosis, 28? 15 h; 6P-naltrex-
`01: controls, 13?4 h; compensated
`cirrhosis, 9+4 h;
`decompensated
`cirrhosis, 1527 h). This might be due
`partly
`to wide data scatter and, in the case of nal-
`trexone,
`to the very low serum levels observed in con-
`trols, making kinetic evaluation more problematic
`in
`this group of subjects.
`ratio
`to naltrexone
`Figure 4 shows the 6P-naltrexol
`in all subjects in-
`2 h after naltrexone administration
`vestigated. This parameter was chosen as a means to
`express, as a single index, the pharmacokinetic
`behav-
`ior, and in particular
`the different concentration
`time-
`course, of the two drugs. Indeed, as is clearly shown,
`the ratio progressively decreased
`from subjects with
`normal
`liver function
`to patients with moderate
`liver
`disease and to patients with severe liver disease, with
`almost no overlap among the different patient groups.
`This confirms
`the existence of a strict relationship be-
`tween the degree of liver function
`impairment and the
`extent of the changes in drug metabolism.
`in the 11
`Linear correlation analysis was performed
`patients with cirrhosis
`in order
`to investigate
`the re-
`lationship between liver function, as expressed by the
`Child-Pugh score, and the main pharmacokinetic
`par-
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`ameters of the two drugs: Cmax, Tmax, AUC, half-life
`of either naltrexone or 6/5naltrexol, and 6/3-naltrexol
`to naltrexone
`ratio at 2 h. The only two parameters
`significantly correlated with the clinical score were 6p-
`naltrexol Tmax (r=0.80, pcO.01) and the 6/Snaltrexol
`to naltrexone
`ratio at 2 h (r=-0.80,
`~~0.01); we se-
`lected the latter parameter, which has the advantage of
`taking into account
`the alterations
`in the time-course
`of both drugs, for subsequent statistical evaluations.
`Figure 5 illustrates
`the significant correlation
`be-
`
`BB-naltrexoltnsltrexone
`
`20
`
`.
`
`at 2 hr
`
`5-
`
`.
`
`I
`
`0
`
`aada
`CIRRHOTICS
`COMP. CIRRHOTICS
`CONTROLS
`161
`15)
`(71
`ratio
`concentrution
`Fig. 4. Plasma ~~-nultrexol~nultrexone
`2 h after oral admin~strution of 100 mg of nultre~one
`in
`control patients, andpatients with compensated and decom-
`pensated cirrhosis. Closed circles represent
`individual data.
`Bars represent meantSD.
`p<O.Ol between controls and
`either group with cirrhosis and between the two groups with
`cirrhosis.
`
`GR-nanrexollnaltrexone
`
`ratio at 2 hr
`
`I
`
`3
`
`5
`
`7
`
`11
`
`13
`
`9
`Clinical score
`Fig. 5. Correlation between
`the plasma 6/Snaltrexol/nal-
`trexone concentration
`ratio 2 h after oral administration of
`100 mg of nu~trexone and the clinical score according to the
`Child-Pugh grading system
`(14)
`in II patients with liver
`cirrhosis. Closed circles represent individual data. Equation
`r= -0.80, p<O.Ol.
`of the regression line: y=4.55-0.387x;
`
`tween the Child-Pugh score and the 6/Gnaltrexol to nal-
`trexone ratio at 2 h in patients with cirrhosis.
`Finally, a significant correlation was found between
`the elimination half-life of caffeine and the 6/I-naltrex-
`01 to naltrexone ratio at 2 h in the nine subjects studied
`(four controls,
`two with compensated
`cirrhosis and
`three with decompensated
`cirrhosis). The equation of
`the regression
`line was y= 10.30-0.227x
`(r= -0.78,
`pCO.02).
`Drug administration was in general very well toler-
`ated. In two patients with decompensated
`cirrhosis,
`naltrexone
`intake was followed by transient nausea and
`irritability
`(patient 9) and by tremors (patient 11). In
`the
`latter patient,
`administration
`of i.m. clonidine
`helped to resolve the picture. No relevant changes in
`serum liver enzymes were observed after drug intake.
`
`Discussion
`The present findings on the plasma time course of nal-
`trexone and its major metabolite, 6/$naltrexol, are con-
`sistent with the prompt
`reductive metabolism of nal-
`trexone
`in subjects with normal
`liver function. This is
`also consistent with previous evidence supporting
`the
`occurrence of very efficient first-pass metabolism by
`the liver (2,7).
`At the present time, there is very little evidence on
`naltrexone pharmacokinetics
`in liver disease, despite
`the evident clinical implications of possible changes in
`drug disposition. As far as we know, this study for the
`first time provides clear evidence about the changes in
`naltrexone bioavailability
`in conditions of impaired
`liver function. The systemic availability of naltrexone
`is markedly
`increased in liver cirrhosis, as reflected by
`the plasma time course of naltrexone and by the data
`on the AUC and Cmax. On the other hand, the sys-
`temic availability of 6D-naltrexol
`is not significantly
`affected by liver disease, even if peak drug concen-
`trations are signi~cantly delayed in patients with cir-
`rhosis. According
`to these findings, the metabolism of
`naltrexone
`to 6/$naltrexol appears
`to be much slower,
`even if it is complete after an appropriate period of
`time.
`Little is known at present about the metabolic path-
`ways involved in naltrexone metabolism and in particu-
`lar about
`the enzyme(s)
`responsible
`for reduction
`to
`6/?-naltrexol; in particular,
`the role of microsomal ver-
`sus non-microsomal
`enzymes has not been clearly
`elucidated so far. At any rate, our findings clearly sug-
`gest an impairment
`in the metabolic conversion of nal-
`trexone
`to 6~-naltrexol
`in liver cirrhosis, which seems
`to parallel the extent of severity of liver disease. It must
`be remembered
`that in our study we only assayed circu-
`lating
`levels of
`free naltrexone
`and 6-naltrexol,
`
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`
`M. Bertolotti et al.
`
`whereas in physiological conditions both drugs under-
`go glucuronoconjugation
`prior
`to urinary
`excretion
`(2). On the other hand, the latter pathway is relatively
`spared even when liver function
`is markedly compro-
`mised; we believe that in the experimental conditions
`of the present study alterations
`in the conjugation
`pathway are unlikely to affect the observed changes in
`drug bioavailability.
`Preliminary evidence from this group has shown a
`subgroup of drug addicts, with otherwise normal
`liver
`function, presenting
`similar metabolic behavior,
`i.e.
`with inversion of the naltrexone
`to 6/?-naltrexol levels
`(16). The reason for this finding is unclear and might
`involve impaired drug metabolism.
`The
`increased
`systemic availability of naltrexone
`relative to 6P-naltrexol might theoretically affect both
`drug efficacy and
`tolerability. The efficacy of drug
`treatment
`should not be impaired
`in these conditions
`because naltrexone
`is known to be a more potent opi-
`ate antagonist
`than 6/?-naltrexol(8); on the other hand,
`the occurrence of side effects due to persistently high
`doses of naltrexone might be increased.
`is de-
`The issue of the hepatotoxicity of naltrexone
`bated; previous
`reports of
`increased
`transaminase
`levels when the drug was given at higher doses (17,18)
`were not confirmed by subsequent studies (2,19,20). In
`our opinion,
`the overall evidence from both literature
`and clinical experience
`suggests that
`treatment with
`naltrexone
`is relatively safe and well tolerated.
`Although
`the present study was obviously not de-
`signed to study naltrexone
`tolerability as its main issue,
`two patients with cirrhosis, both belonging to the Child
`C group, experienced side effects after single administra-
`tion of naltrexone, which were probably
`related to the
`drug and, at least in part, resembled an opiate-with-
`drawal syndrome. We must underline that it seems very
`unlikely
`that patients with advanced, decompensated
`liver cirrhosis would be candidates
`for treatment with
`opiate antagonists;
`indeed, ex-addicts who are suitable
`for such treatment are more likely to have chronic hepa-
`titis, and even patients with chronic cholestatic liver dis-
`ease like primary biliary cirrhosis very rarely present
`with severe liver failure. It would seem appropriate, how-
`ever, to reduce naltrexone dosages in patients with se-
`verely decompensated cirrhosis, if such treatment
`is in-
`dicated, and to monitor liver enzyme levels.
`in the bi-
`Despite the evidence of marked alterations
`oavailability of naltrexone compared
`to 6P-naltrexol
`in
`liver disease, in this study no significant changes could
`be observed with regard to elimination half-life. This
`could be due partly to wide data scatter; furthermore,
`the finding of extremely low levels of naltrexone at the
`latest observation
`times made it difficult
`to perform
`
`510
`
`analysis of this phase. This
`accurate pharmacokinetic
`in control
`subjects, who
`is particularly
`important
`showed naltrexone
`levels at the end of the study which
`were in the same order of magnitude as the sensitivity
`limit of the assay (see the Materials and Methods sec-
`tion).
`With regard to 6/?-naltrexol, the fact that this meta-
`bolite
`is promptly excreted via the urinary
`route
`is
`likely to account for efficient elimination, even in con-
`ditions of liver failure. We need to mention
`that evalu-
`ation of the clearance kinetics of a metabolite can be
`affected by the rate of input of the metabolite
`into the
`central compartment. Therefore, for correct estimation
`of the true clearance rates, other approaches might be
`required
`(like i.v. administration
`of the drug and/or
`multicompartimental
`analysis);
`this was beyond
`the
`aims of the present study, which was mainly focused
`on changes in bioavailability.
`in the time-course of nal-
`The observed alterations
`trexone and 6P-naltrexol were clearly related to the im-
`pairment of liver function, as expressed both by clinical
`judgement (Child-Pugh score) and by caffeine half-life,
`assayed in a subgroup of patients. The most widely
`utilized tests for measuring
`liver function
`(21-23) do
`analyze the kinetics of agents, such as caffeine or anti-
`pyrine, which are poorly extracted by the liver and
`whose metabolism
`is therefore considered
`to be rate-
`limited by the metabolic capacity of the liver (drugs
`with “capacity-dependent”
`metabolism)
`(24). Nal-
`trexone
`is a drug with high hepatic extraction
`and
`whose degradation depends mainly on hepatic blood
`flow (“flow-dependent” metabolism). The analysis of
`its time course and systemic availability (e.g. determi-
`nation of the Cmax and of the 6/?-naltrexollnaltrexone
`ratio 2 h after naltrexone
`intake) might be considered
`an index of liver function which also quantitates,
`to a
`certain extent, hepatic flow-dependent drug degrada-
`tion and/or the degree of porto-systemic
`shunting.
`In conclusion, our finding of altered systemic avail-
`ability of naltrexone
`in liver cirrhosis does not pre-
`clude, in our opinion, utilization of this drug in pa-
`tients with liver disease, even if monitoring
`of liver
`function
`tests and possibly dosage adjustments might
`be advisable.
`
`Acknowledgements
`This work was partly supported by grants from the
`Minister0 dell’Universit8 e della Ricerca Scientifica e
`Tecnologica of Italy (MURST 60%40%).
`
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