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Titolo:
Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19-and CYP3A4/5-phenotyped patients
Autore:
Eap, CB; Bender, S; Gastpar, M; Fischer, W; Haarmann, C; Powell, K; Jonzier-Perey, M; Cochard, N; Baumann, P;
Indirizzi:
Dept Univ Psychiat Adulte, Unite Biochim & Psychopharmacol Clin, Prilly Lausanne, Switzerland Dept Univ Psychiat Adulte Prilly Lausanne Switzerland anne, Switzerland Rhein Landes & Hsch Klin, Essen, Germany Rhein Landes & Hsch Klin Essen Germany ndes & Hsch Klin, Essen, Germany Rhone Poulenc Rorer, Cologne, Germany Rhone Poulenc Rorer Cologne Germany one Poulenc Rorer, Cologne, Germany
Titolo Testata:
THERAPEUTIC DRUG MONITORING
fascicolo: 2, volume: 22, anno: 2000,
pagine: 209 - 214
SICI:
0163-4356(200004)22:2<209:SSPLOT>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VIVO; CYTOCHROME-P450 3A4/5; DEXTROMETHORPHAN; HYDROXYLATION; MEPHENYTOIN; CYP1A2; DEMETHYLATION; DEBRISOQUINE; MOCLOBEMIDE; FLUVOXAMINE;
Keywords:
CYP2D6; CYP2C19; CYP3A4/5; trimipramine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
23
Recensione:
Indirizzi per estratti:
Indirizzo: Eap, CB Hop de Cery, CH-1008 Prilly Lausanne, Switzerland Hop de Cery Prilly Lausanne Switzerland CH-1008 nne, Switzerland
Citazione:
C.B. Eap et al., "Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19-and CYP3A4/5-phenotyped patients", THER DRUG M, 22(2), 2000, pp. 209-214

Abstract

Steady state plasma concentrations of the (L)- and (D)-enantiomers of trimipramine (TRI), desmethyltrimipramine (DTRI), 2-hydroxytrimipramine (TRIOH)and 2-hydroxydesmethyl-trimipramine (DTRIOH) were measured in 27 patients receiving between 300 and 400 mg/day racemic TRI. The patients were phenotyped with dextromethorphan and mephenytoin, and the 8-hour urinary ratios ofdextromethorphan/dextrorphan, dextromethorphan/3-methoxymorphinan, and (S)-mephenytoin/(R)mephenytoin were used as markers of cytochrome P-450IID6 (CYP2D6), CYP3A4/5 and CYP2C19 activities, respectively. One patient was a CYP2D6 and one was a CYP2C19 poor metabolizer. A stereoselectivity in the metabolism of TRI has been found, with a preferential N-demethylation of (D)-TRI and a preferential hydroxylation of (L)-TRI. CYP2D6 appears to be involved in the 2-hydroxylation of (L)-TRI, (L)DTRI and (D)-DTRI, but not of (D)-TRI, as significant correlations were measured between the dextromethorphan/dextrorphan ratios and the (L)-TRI(L)-TRIOH (r = 0.45, p = 0.019), the (L)-DTRI/(L)-DTRIOH (r = 0.47, p = 0.014), and the (D)-DTRI/(D)-DTRIOH (r = 0.51, p = 0.006), but not with the (D)-TRI(D)-TRIOH ratios (r = 0.29, NS). CYP2C19, but not CYP2D6, appears to be involved in the demethylation pathway,with a stereoselectivity toward the (D)-enantiomer of TRI, as a significant positive correlation was calculated between the mephenytoin (S)/(R) ratios and the concentrations to dose-to-weight ratios of (D)-TRT (r = 0.69, p =0.00006). CYP3A4/5 appears to be involved in the metabolism of (L)-TRT to a presently not determined metabolite. The CYP2D6 poor metabolizer had the highest (L)DTRI and (D)-DTRI concentrations to dose-to-weight ratios, and the CYP2C19 poor metabolizer had the highest (L)-TRI and (D)-TRI concentrations to dose-to-weight ratios of the group.

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Documento generato il 23/01/20 alle ore 03:26:56