三唑类抗真菌药物伏立康唑的药代动力学、代谢和生物利用度与 CYP2C19 基因型的关系。
Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype.
机构信息
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
出版信息
Br J Clin Pharmacol. 2009 Dec;68(6):906-15. doi: 10.1111/j.1365-2125.2009.03534.x.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- Pharmacokinetic variability of voriconazole is largely caused by CYP3A4- and CYP2C19-mediated metabolism. * Oral bioavailability of voriconazole has been claimed to be almost 100%, thus facilitating a change from intravenous to oral application without dose adjustment.
WHAT THIS STUDY ADDS
- For the first time voriconazole exposure after intravenous and oral administration in relation to CYP2C19 activity is reported. * In addition, the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C19 genotype. * Enterohepatic circulation of both hydroxylated metabolites must be anticipated.
AIMS
The aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole.
METHODS
In a single-centre, open-label, two-period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high-performance liquid chromatography coupled to mass spectroscopy.
RESULTS
Absolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N-oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N-oxidation [48.8 ml min(-1) (30.5, 67.1) vs. 6.1 ml min(-1) (4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity.
CONCLUSIONS
Independent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N-oxidation, both influenced by the CYP2C19 genotype.
已知信息：
伏立康唑的药代动力学变异性主要由 CYP3A4 和 CYP2C19 介导的代谢引起。
伏立康唑的口服生物利用度几乎为 100%，因此无需调整剂量即可从静脉应用改为口服应用。
本研究新增信息：
首次报道了静脉和口服给药后与 CYP2C19 活性相关的伏立康唑暴露情况。
此外，主要的代谢途径是羟化，似乎受 CYP2C19 基因型的影响。
两种羟化代谢物都必须预期有肠肝循环。
目的：
本研究旨在比较健康个体中单剂量口服和静脉（i.v.）给予伏立康唑后的药代动力学，并根据细胞色素 P450（CYP）2C19 基因型进行分层。
此外，还研究了口服和 i.v.给予伏立康唑后可能的代谢途径及其对 CYP2C19 基因型的调节。
方法：
在一项单中心、开放标签、两周期交叉研究中，20 名参与者随机接受单剂量 400 mg 伏立康唑口服和 400 mg 伏立康唑静脉给药。
在给药后 96 小时内采集血样和尿样，并通过高效液相色谱-质谱联用定量检测伏立康唑和三种主要代谢物。
结果：
伏立康唑的绝对口服生物利用度为 82.6%（74.1，91.0）。
在 CYP2C19 弱代谢者中为 94.4%（78.8，109.9），在广泛代谢者中为 75.2%（62.9，87.4）。
与伏立康唑及其 N-氧化物不同，两种羟化代谢物的血浆浓度在 24 小时后显示出较大的第二峰。
无论给药途径如何，静脉给药后伏立康唑的部分代谢羟化作用比 N-氧化作用高 8 倍[48.8 ml min^-1（30.5，67.1）比 6.1 ml min^-1（4.1，8.0）]。
代谢物的形成与 CYP2C19 活性有关。
结论：
无论给药途径如何，CYP2C19 弱代谢者的伏立康唑暴露量均比广泛代谢者高 3 倍。
伏立康唑具有较高的生物利用度，CYP2C19 基因型之间无明显差异。
伏立康唑消除的羟化途径超过 N-氧化，两者均受 CYP2C19 基因型的影响。
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