Drug–Drug Interaction – Enzyme Induction

PURPOSE AND RATIONALE Enzyme induction can be considered a natural defense mechanism. Xenobiotics that enter the human body via ingestion are subjected to metabolism firstly by the drug metabolizing enzymes (DME) in the intestinal epithelium, and may be removed by the p-glycoprotein (Pgp) from the epithelial cells back into the lumen. The xenobiotics that escape intestinal metabolism and efflux enter into the portal circulation are subjected to metabolism by the liver – the organ specializing in xenobiotic metabolism, before entering the system circulation. As a defense mechanism, the DME and Pgp can be induced, leading to a higher rate and capacity of xenobiotics elimination. Enzyme induction is generally considered an adverse drug property. The major consequences of enzyme induction are pharmacokinetic drug–drug interactions and liver toxicity. Adverse drug–drug interactions occur mainly due to pharmacokinetic drug–drug interactions – the alteration of the rate of metabolism of one drug by a co-administered drug, or pharmacological drug–drug interactions – toxicity occurring due to the combined pharmacological effects of the interacting drugs. There are two major mechanisms of pharmacokinetic drug– drug interactions: inhibitory and inductive drug–drug interactions (Li 1998): Inhibitory drug–drug interactions: One drug may inhibit the metabolism of a co-administered drug, leading to a higher than expected level of the affected drug. Drug toxicity is the major consequence of inhibitory drug–drug interactions, as the affected drug may exceed the safe level. Inductive drug–drug interactions: When a drug induces DME, it has the potential to cause inductive drug–drug interactions. A drug that induces a DME may lead to faster metabolic elimination of a co-administered drug which is a substrate of the affected DME, which may result in a loss of efficacy. The known human enzyme inducers are tabulated in Table 1. Enzyme induction in laboratory animals is general associated with liver enlargement which is considered a toxic endpoint. A large percentage of drugs that are associated with idiosyncratic liver toxicity are also enzyme inducers (Li 2002). The co-existence of enzyme induction and hepatotoxicity for drugs is illustrated in Table 1. The mechanistic link between enzyme induction and liver toxicity, if any, is yet to be established. There may be a true link as enzyme induction represents a disturbance of the homeostasis of the liver. The induced enzyme may activate certain environmental or endogenous toxicants. Alternatively, as the drugs that are associated with severe liver toxicity are administered at relatively high doses, the enzyme induction may be related more to the high dosages and is independent of the liver toxicity. However, because of the apparent relationship between enzyme induction and hepatotoxicity, some researchers in drug development view enzyme induction potential as an indicator of hepatotoxic potential. The mechanism of P450 induction is an area of intensive research activities. There is a general finding, with some exceptions, that enzyme induction occurs via the binding of the inducers to nuclear receptors that subsequently leads to increased gene expression and protein synthesis (Waxman 1999; Honkakoski and Negishi 2000; Tirona et al. 2003; Wang et al. 2004). The key receptors for enzyme inducers are tabulated in Table 2. These receptors are as follows: