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Titolo:
Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients
Autore:
Foster, DJR; Somogyi, AA; Dyer, KR; White, JM; Bochner, F;
Indirizzi:
Univ Adelaide, Dept Clin & Expt Pharmacol, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 ol, Adelaide, SA 5005, Australia Univ Adelaide, Dept Psychol, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 ol, Adelaide, SA 5005, Australia Royal Adelaide Hosp, Dept Clin Pharmacol, Adelaide, SA 5000, Australia Royal Adelaide Hosp Adelaide SA Australia 5000 elaide, SA 5000, Australia
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 5, volume: 50, anno: 2000,
pagine: 427 - 440
SICI:
0306-5251(200011)50:5<427:SPO(A(>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; PLASMA-PROTEIN BINDING; HUMAN LIVER-MICROSOMES; N-DEMETHYLATION; ALPHA-1-ACID GLYCOPROTEIN; CYTOCHROME-P450 3A4; ACID GLYCOPROTEIN; DL-METHADONE; OPIATE USERS; CHRONIC PAIN;
Keywords:
2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; drug dependence; metabolism; methadone; pharmacokinetics; protein binding; stereoselectivity;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Foster, DJR Univ Adelaide, Dept Clin & Expt Pharmacol, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 , SA 5005, Australia
Citazione:
D.J.R. Foster et al., "Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients", BR J CL PH, 50(5), 2000, pp. 427-440

Abstract

Aims To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein bindingwas examined using ultrafiltration, and plasma alpha (1)-acid glycoproteinconcentrations were quantified by radial immunoassay. Results (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUC(tauu)(ss) (167%) was significantly (P < 0.001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUC(tau)(ss), steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 01:00:06