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Titolo:
EFFECT OF CYP3A INHIBITION ON VESNARINONE METABOLISM IN HUMANS
Autore:
WANDEL C; LANG CC; COWART DC; GIRARD AF; BRAMER S; FLOCKHART DA; WOOD AJJ;
Indirizzi:
VANDERBILT UNIV,DIV CLIN PHARMACOL,MED RES BLDG 1,23RD AVE S PIERCE AVE NASHVILLE TN 37232 VANDERBILT UNIV,DIV CLIN PHARMACOL NASHVILLE TN 37232 OTSUKA AMER PHARMACEUT INC ROCKVILLE MD 00000 GEORGETOWN UNIV,DEPT CLIN PHARMACOL WASHINGTON DC 20057
Titolo Testata:
Clinical pharmacology and therapeutics
fascicolo: 5, volume: 63, anno: 1998,
pagine: 506 - 511
SICI:
0009-9236(1998)63:5<506:EOCIOV>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
ERYTHROMYCIN BREATH TEST; IN-VIVO PROBES; CYCLOSPORINE; DEHYDROGENATION; MIDAZOLAM; OPC-8212;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
19
Recensione:
Indirizzi per estratti:
Citazione:
C. Wandel et al., "EFFECT OF CYP3A INHIBITION ON VESNARINONE METABOLISM IN HUMANS", Clinical pharmacology and therapeutics, 63(5), 1998, pp. 506-511

Abstract

Objective: To identify the cytochrome P450 (CYP) enzymes involved in the conversion of vesnarinone to its main primary metabolite OPC-18692and to investigate the effect of CYP3A inhibition on the pharmacokinetics of vesnarinone in vivo. Methods: Formation of the primary vesnarinone metabolite OPC-18692 was measured in microsomes from AHH-1 TK+/- cells heterologously expressing CYP1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4. The pharmacokinetics of vesnarinone and OPC-18692were defined for 12 healthy white men after oral administration of 60mg vesnarinone before and after CYP3A inhibition, which was produced by pretreatment with erythromycin, CYP3A inhibition was verified with the erythromycin breath test. Results: In vitro, expressed CYP2E1 and CYP3A4 produced significant amounts of OPC-18692 with the higher formation rate observed by CYP3A4 (12.3 pmol/pmol CYP3A4 per 2 hours versus1 pmol/pmol CYP2E1 per 2 hours). In vivo, the area under the concentration-time curve extrapolated to infinity (AUC[infinity]) of vesnarinone after pretreatment with erythromycin increased from 133 +/- 26 mu g.hr/ml to 202 +/- 47 mu g.hr/ml (p < 0.001), and the half-life increased from 36.5 +/- 9.6 hours to 46.2 +/- 9.2 hours (p < 0.01). Clearancedecreased from 372 +/- 68 ml/min to 256 +/- 49 ml/min (p < 0.001). These changes in the disposition of vesnarinone were accompanied by a decrease in plasma concentration of the metabolite OPC-18692 so that theAUC(0-48) was reduced from 1311 +/- 513 mu g.hr/ml to 850 +/- 148 mu g.hr/ml (p < 0.001). The total amount of vesnarinone excreted in the urine up to 168 hours after administration increased after erythromycinpretreatment (p < 0.001), Although renal clearance did not change, OPC-18692 was not detectable in the urine. The erythromycin breath test showed significant inhibition after pretreatment with erythromycin (p < 0.001). Conclusions: CYP2E1 and CYP3A4 are involved in the phase I metabolism of vesnarinone. Inhibition of CYP3A activity in vivo increases the plasma concentration of vesnarinone and delays its elimination in humans so that monitoring of its plasma levels may be helpful in preventing concentration-related toxicity when CYP3A activity is impaired. Whether CYP3A induction and altered CYP2E1 activity may also changethe in viva disposition of vesnarinone remains to be determined.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/01/20 alle ore 20:03:41