Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components
Autore:
Eagling, VA; Profit, L; Back, DJ;
Indirizzi:
Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside,England Univ Liverpool Liverpool Merseyside England L69 3GE E, Merseyside,England
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 4, volume: 48, anno: 1999,
pagine: 543 - 552
SICI:
0306-5251(199910)48:4<543:IOTCMA>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
MULTIDRUG-RESISTANCE GENE; ACTIVE ANTIRETROVIRAL THERAPY; HUMAN LIVER-MICROSOMES; FIRST-PASS METABOLISM; CELL-LINE CACO-2; FELODIPINE INTERACTION; CYTOCHROME-P450 3A4; ORAL AVAILABILITY; CYCLOSPORINE; EXPRESSION;
Keywords:
CYP3A4; grapefruit juice; P-glycoprotein;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Back, DJ Univ Liverpool, Dept Pharmacol & Therapeut, Ashton St, Liverpool L69 3GE, Merseyside, England Univ Liverpool Ashton St Liverpool Merseyside England L69 3GE and
Citazione:
V.A. Eagling et al., "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components", BR J CL PH, 48(4), 1999, pp. 543-552

Abstract

Aims Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are both expressed in the intestinal mucosa and present a barrier to oral drug delivery. CYP3A4 and P-gp share both overlapping tissue distribution and substrate specificity. Grapefruit juice interactions with CYP3A4 substrates are well documented and occur as a consequence of down regulation of intestinal CYP3A4. The aim of the present study was to screen grapefruit juice components against the CYP3A4-mediated metabolism and P-gp mediated transport of the HIV-1 protease inhibitor saquinavir. Methods Five grapefruit juice components: quercetin, naringin, naringenin,6',7'-dihydroxybergamottin and bergamottin were screened as potential inhibitors of the metabolism of saquinavir by human liver microsomes. The knownCYP3A4 inhibitor ketoconazole was also screened for inhibitory potential. These compounds were also screened as modulators of P-gp activity by assessing the directional transport of saquinavir across Caco-2 cell monolayers which express P-gp. The effect of verapamil, a known modulator of P-gp function, was also determined in these cell lines. Results On preincubation, 6',7'-dihydroxybergamottin and bergamottin inhibited the metabolism of saquinavir, with IC50 values of 0.33 +/- 0.23 mu M and 0.74 +/- 0.13 mu M, respectively (n = 3). Ketoconazole achieved an IC50 of 0.55 +/- 0.12 mu M (n = 4). The other compounds studied failed to reach IC50 at concentrations of up to 100 mu M The transport of saquinavir in thebasolateral-->apical (BL-->AP) direction exceeded that in the apical -->basolateral direction (AP-->BL), with apparent permeability coefficients of 199.2 +/- 15.8 x 10(-7) cm s(-1) and 8.00 +/- 1.13 x 10(-7) cm s(-1), respect ively (n = 3) which is indicative of a polarized efflux mechanism. The ratio of BL-->AP/AP-->BL for saquinavir was 25, but in the presence of verapamil and ketoconazole this ratio was reduced to 3.6 and 4.0, respectively (n= 3), indicating extensive inhibition of P-gp mediated saquinavir efflux. Of the grapefruit juice components studied only naringin and 6',7'-dihydroxybergamottin had any appreciable effect, reducing the ratio to 7.6 and 7.1,respectively (n = 3); but this was due solely to increased AP-->BL transport. Conclusions Grapefruit juice components inhibit CYP3A4-mediated saquinavirmetabolism and also modulate, to a limited extent, P-gp mediated saquinavir transport in Caco-2 cell monolayers. The in vivo effects of grapefruit juice coadministration are most likely the result of effects on CYP3A4 (inhibition and down regulation) and only to a minor extent on modulation of P-gpfunction.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 13:46:43