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Titolo:
Neither dapsone hydroxylation nor cortisol 6 beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors
Autore:
Gass, RJA; Gal, J; Fogle, PW; Detmar-Hanna, D; Gerber, JG;
Indirizzi:
Univ Colorado, Hlth Sci Ctr, Div Clin Pharmacol, Dept Med, Denver, CO 80262 Univ Colorado Denver CO USA 80262 n Pharmacol, Dept Med, Denver, CO 80262 Univ Colorado, Hlth Sci Ctr, Div Infect Dis, Dept Med, Denver, CO 80262 USA Univ Colorado Denver CO USA 80262 ect Dis, Dept Med, Denver, CO 80262 USA
Titolo Testata:
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 9-10, volume: 54, anno: 1998,
pagine: 741 - 747
SICI:
0031-6970(199811/12)54:9-10<741:NDHNC6>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
IMMUNODEFICIENCY-VIRUS INFECTION; ERYTHROMYCIN BREATH TEST; IN-VIVO PROBES; RITONAVIR ABT-538; N-HYDROXYLATION; METABOLISM; INDINAVIR; PHARMACOKINETICS; DISPOSITION; THERAPY;
Keywords:
CYP3A4; dapsone; N-hydroxylation; cortisol beta-hydroxylation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Gerber, JG Univ,4200rado, Hlth Sci Ctr, Div Clin Pharmacol, Dept Med, Campus Box C-237 Univ Colorado Campus Box C-237,4200 E 9th Ave Denver CO USA 80262
Citazione:
R.J.A. Gass et al., "Neither dapsone hydroxylation nor cortisol 6 beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors", EUR J CL PH, 54(9-10), 1998, pp. 741-747

Abstract

Objective: This study examined the use of dapsone N-hydroxylation and cortisol 6 beta-hydroxylation, well accepted in vivo probes of cytochrome P4503A4 (CYP3A4) activity, on defining the effect of three HIV protease inhibitors on CYP3A4 activity. Methods: Subjects from University Hospital Infectious Disease Clinic aboutto be started on indinavir, and subjects from two clinical studies, one using ritonavir and the other using amprenavir, were recruited to participatein the study. Subjects received dapsone 100 mg p.o. followed by an 8-h urine collection for dapsone, dapsone N-hydroxylamine, cortisol, and 6 beta-hydroxycortisol concentrations before HIV protease inhibitor administration, and 3-4 weeks into receiving HIV protease inhibitors. Results: None of the HIV protease inhibitors demonstrated statistically significant alterations in dapsone recovery ratio and 6 beta-hydroxycortisol/cortisol ratio. In fact, with ritonavir, the dapsone recovery ratio tended to increase rather than decrease, suggesting induction. These negative results were found despite evidence of CYP3A4 inhibition by these three HIV protease inhibitors via published drug-drug interactions with drugs that are substrates for CYP3A4. Conclusions: These in vivo assays used to probe CYP3A4 activity are suboptimal, most likely because of the presence of extrahepatic sites of metabolism for both dapsone and cortisol, and multiple CYP isozymes involved in dapsone N-hydroxylation.

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Documento generato il 09/07/20 alle ore 18:51:17