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- Title
Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components.
- Authors
Eagling; Profit; Back
- 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 known CYP3A4 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 IC[sub 50] values of 0.33±0.23 μm and 0.74±0.13 μm, respectively (n=3). Ketoconazole achieved an IC[sub 50] of 0.55±0.12 μm (n=4). The other compounds studied failed to reach IC[sub 50] at concentrations of up to 100 μm. The transport of saquinavir in the basolateral→apical (BL→AP) direction exceeded that in the apical →basolateral direction (AP→BL), with apparent permeability coefficients of 199.2±15.8×10[sup -7] cm s[sup -1] and 8.00±1.13×10[sup -7] cm s[sup -1], respectively (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 ...
- Subjects
GRAPE juice; P-glycoprotein; PROTEASE inhibitors; HEALTH
- Publication
British Journal of Clinical Pharmacology, 1999, Vol 48, Issue 4
- ISSN
0306-5251
- Publication type
Article