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Titolo:
HUMAN LIVER MICROSOMAL METABOLISM OF PACLITAXEL AND DRUG-INTERACTIONS
Autore:
DESAI PB; DUAN JZ; ZHU YW; KOUZI S;
Indirizzi:
UNIV CINCINNATI,MED CTR,COLL PHARM,DIV PHARMACEUT SCI,3223 EDEN AVE CINCINNATI OH 45267 NE LOUISIANA UNIV,SCH PHARM,DIV BASIC PHARMACEUT SCI MONROE LA 71209
Titolo Testata:
European journal of drug metabolism and pharmacokinetics
fascicolo: 3, volume: 23, anno: 1998,
pagine: 417 - 424
SICI:
0378-7966(1998)23:3<417:HLMMOP>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
MULTIDRUG-RESISTANCE; CYTOCHROME-P450 3A4; TAXOL METABOLISM; P-GLYCOPROTEIN; BREAST-CANCER; PHASE-I; PHARMACOKINETICS; TAMOXIFEN; PHARMACODYNAMICS; VERAPAMIL;
Keywords:
PACLITAXEL; HUMAN MICROSOMES; HEPATIC METABOLISM; DRUG INTERACTIONS; TAMOXIFEN; R-VERAPAMIL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
31
Recensione:
Indirizzi per estratti:
Citazione:
P.B. Desai et al., "HUMAN LIVER MICROSOMAL METABOLISM OF PACLITAXEL AND DRUG-INTERACTIONS", European journal of drug metabolism and pharmacokinetics, 23(3), 1998, pp. 417-424

Abstract

The aim of this study was to investigate the influence of several anticancer drugs and investigational multidrug resistance (MDR) reversingagents on the hepatic metabolism of paclitaxel (Taxol) to its primarymetabolites, 6 alpha-hydroxypaclitaxel (metabolite, M-A) and 3'-p-hydroxypaclitaxel (metabolite, M-B). There is significant inter-individual variability associated with the levels of these two metabolites. In many cases, 6 alpha-hydroxypaclitaxel has been observed to be the predominant metabolite, in others, 3'-p-hydroxypaclitaxel has been the principal metabolite. The formation of 6a-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel is catalyzed by cytochrome P450 isozymes CYP2C8 and CYP3A4, respectively. A number of factors, including co-administration of drugs and adjuvants, are known to influence the activity of these isozymes. Therefore, the influence of MDR reversing agents, R-verapamil, cyclosporin A (CsA) and tamoxifen and anti-cancer drugs doxorubicin, etoposide (VP-16) and cisplatin on paclitaxel metabolism was assessed employing human liver microsomes in vitro. Paclitaxel (10 mu M) was incubated with human liver microsomes (1 mg protein, -0.34 nmol CYP) in the presence of a NADPH generating system at 37 degrees C for 1 h, with and without the: presence of interacting drug. Controls included incubations with quercetin and ketoconazole, known inhibitors of 6 alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel formation, respectively. Atthe end of the incubation period, paclitaxel and the metabolites wereextracted in ethyl acetate and analyzed employing an HPLC method. Significant inhibition of paclitaxel conversion to 6 alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel was observed in the presence of R-verapamil, tamoxifen and VP-16 (P 0.005). Doxorubicin significantly inhibited the formation of 3'-p-hydroxypaclitaxel and CsA inhibited the formation of 6 alpha-hydroxypaclitaxel (P 0.005). This study demonstrates that co-administration of several of the above listed compounds could lead to significant changes in the pharmacokinetics of paclitaxel.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 10:05:46