Wandel C, Böcker R, Böhrer H, Browne A, Rügheimer E, Martin E
Department of Anaesthesia, University of Heidelberg, Germany.
Br J Anaesth. 1994 Nov;73(5):658-61. doi: 10.1093/bja/73.5.658.
Distribution volumes and metabolism determine the pharmacokinetics of midazolam. Cytochrome P450 3A4 has been considered a significant enzyme in its metabolism. Using heterologously expressed cytochrome P450 enzymes, we have confirmed the additional involvement of cytochromes P450 3A3 and 3A5 in the hydroxylation of the midazolam. Whereas cytochrome P450 3A3 metabolized midazolam to the same extent as cytochrome P450 3A4, cytochrome P450 3A5 increased its metabolism by a factor of 2.7. The relationship of alpha- to 4-hydroxylation of midazolam was approximately 1.3 for cytochromes P450 3A3 and 3A4, and approximately 8.8 for 3A5. The primary location of cytochromes P450 3A3 and 3A4 is the liver in contrast with cytochrome P450 3A5, which occurs predominantly in the kidney. Therefore, further in vivo study is required to prove conclusively that enzymes in the kidney are involved in the metabolism of midazolam. Nitrendipine itself is metabolized by cytochrome P450 3A enzymes and this was shown to inhibit human liver microsomal hydroxylation of midazolam and preferentially alpha-hydroxylation by about 77%. 4-Hydroxylation was inhibited to 32% of control by nitrendipine. In contrast with inhibition of 4-hydroxylation, alpha-hydroxylation would appear to be competitively inhibited. These findings may be relevant to drug interactions in combined therapy.
分布容积和代谢决定了咪达唑仑的药代动力学。细胞色素P450 3A4被认为是其代谢过程中的一种重要酶。利用异源表达的细胞色素P450酶，我们已证实细胞色素P450 3A3和3A5也参与了咪达唑仑的羟基化反应。细胞色素P450 3A3对咪达唑仑的代谢程度与细胞色素P450 3A4相同，而细胞色素P450 3A5使咪达唑仑的代谢增加了2.7倍。对于细胞色素P450 3A3和3A4，咪达唑仑的α-羟基化与4-羟基化的比例约为1.3，而对于3A5则约为8.8。与主要存在于肾脏的细胞色素P450 3A5不同，细胞色素P450 3A3和3A4主要位于肝脏。因此，需要进一步的体内研究来确凿证明肾脏中的酶参与了咪达唑仑的代谢。尼群地平本身由细胞色素P450 3A酶代谢，并且已证明它能抑制人肝微粒体对咪达唑仑的羟基化反应，对α-羟基化的抑制作用尤为明显，约为77%。尼群地平将4-羟基化抑制至对照的32%。与对4-羟基化的抑制作用不同，α-羟基化似乎是竞争性抑制。这些发现可能与联合治疗中的药物相互作用有关。
