Lin J H, Lu A Y
Merck Research Laboratories, West Point, Pennsylvania, USA.
Clin Pharmacokinet. 1998 Nov;35(5):361-90. doi: 10.2165/00003088-199835050-00003.
The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an important role in the oxidative metabolism of drugs. Each CYP isoform possesses a characteristic broad spectrum of catalytic activities of substrates. Whenever 2 or more drugs are administered concurrently, the possibility of drug interactions exists. The ability of a single CYP to metabolise multiple substrates is responsible for a large number of documented drug interactions associated with CYP inhibition. In addition, drug interactions can also occur as a result of the induction of several human CYPs following long term drug treatment. The mechanisms of CYP inhibition can be divided into 3 categories: (a) reversible inhibition; (b) quasi-irreversible inhibition; and (c) irreversible inhibition. In mechanistic terms, reversible interactions arise as a result of competition at the CYP active site and probably involve only the first step of the CYP catalytic cycle. On the other hand, drugs that act during and subsequent to the oxygen transfer step are generally irreversible or quasi-irreversible inhibitors. Irreversible and quasi-irreversible inhibition require at least one cycle of the CYP catalytic process. Because human liver samples and recombinant human CYPs are now readily available, in vitro systems have been used as screening tools to predict the potential for in vivo drug interaction. Although it is easy to determine in vitro metabolic drug interactions, the proper interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles. From the viewpoint of drug therapy, to avoid potential drug-drug interactions, it is desirable to develop a new drug candidate that is not a potent CYP inhibitor or inducer and the metabolism of which is not readily inhibited by other drugs. In reality, drug interaction by mutual inhibition between drugs is almost inevitable, because CYP-mediated metabolism represents a major route of elimination of many drugs, which can compete for the same CYP enzyme. The clinical significance of a metabolic drug interaction depends on the magnitude of the change in the concentration of active species (parent drug and/or active metabolites) at the site of pharmacological action and the therapeutic index of the drug. The smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences. Thus, careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential.
细胞色素P450（CYP）构成了一个同工酶超家族，在药物的氧化代谢中发挥着重要作用。每种CYP同工酶都具有底物催化活性的特征性广谱性。当同时使用两种或更多种药物时，就存在药物相互作用的可能性。单一CYP代谢多种底物的能力导致了大量与CYP抑制相关的已记录药物相互作用。此外，长期药物治疗后几种人类CYP的诱导也可能导致药物相互作用。CYP抑制的机制可分为3类：（a）可逆抑制；（b）准不可逆抑制；（c）不可逆抑制。从机制上讲，可逆相互作用是由于在CYP活性位点的竞争而产生的，可能仅涉及CYP催化循环的第一步。另一方面，在氧转移步骤期间及之后起作用的药物通常是不可逆或准不可逆抑制剂。不可逆和准不可逆抑制至少需要一个CYP催化过程循环。由于现在很容易获得人类肝脏样本和重组人类CYP，体外系统已被用作筛选工具来预测体内药物相互作用的可能性。虽然很容易确定体外代谢药物相互作用，但要将体外相互作用数据正确解释并外推到体内情况，需要对药代动力学原理有很好的理解。从药物治疗的角度来看，为了避免潜在的药物-药物相互作用，开发一种新的候选药物是可取的，该药物不是强效的CYP抑制剂或诱导剂，并且其代谢不容易被其他药物抑制。实际上，药物之间相互抑制引起的药物相互作用几乎是不可避免的，因为CYP介导的代谢是许多药物消除的主要途径，这些药物可能竞争相同的CYP酶。代谢药物相互作用的临床意义取决于活性物质（母体药物和/或活性代谢物）在药理作用部位浓度变化的幅度以及药物的治疗指数。毒性浓度和有效浓度之间的差异越小，药物相互作用产生严重临床后果的可能性就越大。因此，在药物开发的早期阶段仔细评估新候选药物的潜在药物相互作用至关重要。
