西柚汁成分对HIV-1蛋白酶抑制剂saquinavir cyp3a4介导的代谢和p -糖蛋白介导的转运的抑制
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鹰队VA，利润L，后DJ
西柚汁成分对HIV-1蛋白酶抑制剂saquinavir cyp3a4介导的代谢和p -糖蛋白介导的转运的抑制
中华临床药物学杂志1999 10月;48(4):543-52。
- PubMed ID
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10583025 (PubMed视图］
- 摘要
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目的:细胞色素P450 3A4 (CYP3A4)和p -糖蛋白(P-gp)均在肠黏膜表达，并对口服给药产生障碍。CYP3A4和P-gp具有重叠的组织分布和底物特异性。葡萄柚汁与CYP3A4底物的相互作用是由肠道CYP3A4下调引起的。本研究的目的是筛选西柚汁成分对抗cyp3a4介导的代谢和P-gp介导的HIV-1蛋白酶抑制剂saquinavir的转运。方法:筛选槲皮素、柚皮素、柚皮素、6′、7′-二羟基佛手柑素和佛手柑素5种西柚汁成分作为人肝微粒体对沙奎那韦代谢的潜在抑制剂。已知的CYP3A4抑制剂酮康唑也被筛选抑制潜力。通过评估saquinavir在表达P-gp的Caco-2细胞单层中的定向转运，这些化合物也被筛选为P-gp活性的调节剂。已知的P-gp功能调节剂维拉帕米的作用也在这些细胞系中确定。结果:预孵育时，6'，7'-二羟基佛手柑素和佛手柑素对沙奎那韦的代谢有抑制作用，IC50值分别为0.33+/-0.23 muM和0.74+/-0.13 muM (n=3)。酮康唑的IC50为0。 55+/-0.12 muM (n=4). The other compounds studied failed to reach IC50 at concentrations of up to 100 muM. 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+/-15.8x10-7 cm s-1 and 8.00+/-1. 13x10-7 cm s-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 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 saquinavir metabolism 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-gp function.