The pharmacokinetics of paroxetine in patients with liver cirrhosis

Krastev, Zahariy; Terziivanov, D; Vlahov, V.; Maleev, A; Greb, W. H.; Eckl, Katja Martina; Dierdorf, H.‐D.; Wolf, David S.

doi:10.1111/j.1600-0447.1989.tb07182.x

Cited by 27 publications

(9 citation statements)

References 2 publications

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“…Patients with prevailing liver insufficiency show altered pharmacokinetics for psychoactive drugs, including the SSRIs (Holm et al 1986; Krastev et al 1989; Stoeckel et al 1990). Nevertheless, and not taking the likely different pharmacodynamic effects of hepatic encephalopathy subjects into account, these pharmacokinetic aberrations have been suggested to be of minor importance in patients with impaired liver function (Hale 1993; DeVane 1994).…”

Section: Discussionmentioning

confidence: 99%

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Kugelberg

Apelqvist

Carlsson

et al. 2006

Basic Clin Pharma Tox

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Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and shamoperated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S-and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups.

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Section: Discussionmentioning

confidence: 99%

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Kugelberg

Apelqvist

Carlsson

et al. 2006

Basic Clin Pharma Tox

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“…The pharmacokinetics of paroxetine following a single oral dose of 20mg were studied in a group of 12 subjects with biopsy proven hepatic cirrhosis (17). The data obtained (Table 11) indicated that in this group of cirrhotic subjects the pharmacokinetics of paroxetine are unaltered compared with data obtained in healthy subjects.…”

Section: Subjects With Hepatic Diseasementioning

confidence: 98%

A review of the metabolism and pharmacokinetics of paroxetine in man

Kaye

Haddock

Langley

et al. 1989

Acta Psychiatr Scand

244

159

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Acta psychiatr. scand: 80 (supp. 350): 60-75 ABSTRACT -Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeuticallyrelevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to theclinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokineticparameters are not predictable from single-dose data. In many subjects, daily administration of 20-50mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single doses. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events). Paroxetine (Fig. l), a potent, selective 5-HT uptake inhibitor, currently being developed as a n antidepressant d r u g (1,2), has been review are in terms of the pure free base. extensively studied in man to examine its metabolism andpharmacokinetics. This review provides a summary of the key findings to date, extending earlier observations (3,4). Paroxetine is administered as its hydrochloride salt (BRL 29060A), but doses quoted throughout this Analytical methodology Paroxetinecan be determined in biologi...

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“…Patients with impaired liver function often show alterations in pharmacokinetic parameters for the majority of psychoactive drugs, also including the novel monoamine-acting antidepressants (Holm et al 1986;Krastev et al 1989;Royer et al 1989;DeVane et al 1990;Stoeckel et al 1990;Dalho¤ et al 1991;Ferry et al 1994;Orlando et al 1995). However, somewhat surprisingly, such aberrations in pharmacokinetics are often suggested to be of minor clinical importance (Hale 1993;DeVane 1994).…”

Section: Discussionmentioning

confidence: 94%

Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges

et al. 1999

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The present study show altered but opposite behavior in PCS rats, when challenged with either venlafaxine or citalopram, compared to PCS control rats. These findings therefore support the contention that caution should be advocated when CNS monoamine active drugs are used in liver-impaired subjects until better delineation of the combined pharmacodynamic and pharmacokinetic outcome for each such drug in this condition has been made.

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The pharmacokinetics of paroxetine in patients with liver cirrhosis

Cited by 27 publications

References 2 publications

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

A review of the metabolism and pharmacokinetics of paroxetine in man

Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges

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