The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans
The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans
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DOI：
10.1046/j.1365-2125.1999.00999.x
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发表时间：
1999-08-01
影响因子：
3.4
通讯作者：
Lennernäs, H
中科院分区：
文献类型：
--
作者：
Sandström, R;Knutson, TW;Lennernäs, H
目的研究酮康唑对人空肠通透性和（R）-和（S）-维拉帕米首过代谢的影响。每次灌注持续200 min，并分为两个阶段，每个阶段100 min。在两个阶段中，（R/S）-维拉帕米的入口浓度均为120 mg 1（-1），在第2阶段中加入40 mg 1（-1）的酮康唑。（R/S）-维拉帕米也以5 mg的短静脉内输注给药，结果（R）-和（S）-去甲维拉帕米的有效空肠渗透率（Peff）分别为0.001和0.001，P < 0.01，P维拉帕米不受第2阶段加入酮康唑的影响，表明酮康唑对P-糖蛋白介导的外排无影响。然而，在存在酮康唑的情况下，出口空肠灌流液中（R）-和（S）-去甲维拉帕米的出现率均下降。尽管加入了低剂量的酮康唑，（R）-和（S）-维拉帕米的血浆吸收率仍增加，表明酮康唑抑制了（R/S）-维拉帕米的肠壁代谢。它可能通过抑制维拉帕米的肠壁代谢，确实增加了进入体循环的总转运（生物利用度）。这可能是由于酮康唑在人体内作为P-糖蛋白抑制剂的效力低于CYP 3A 4。
Aims The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first-pass metabolism of (R)-and (S)-verapamil in humans.Methods A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)-verapamil was 120 mg 1(-1) in both periods, and ketoconazole was added at 40 mg 1(-1) in period 2. (R/S)-verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)- and (S)-norverapamil were also estimated in the outlet jejunal perfusate.Results The effective jejunal permeability (Peff) of both (R)- and (S)-verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P-glycoprotein mediated efflux. However, the appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)- and (S)-verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)-verapamil by ketoconazole.Conclusions Ketoconazole did not affect the jejunal Peff of (R/S)-verapamil, but: it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P-glycoprotein in than of CYP3A4 in vivo in humans.