ABSTRACT

InteractionsCYP-mediated drug interactions are very common because most therapies, e.g., cancer and antiretrovirals, entail multiple drugs for effective treatment (Antoniou and Tseng, 2005; Walubo, 2007). These drug interactions are further complicated, because there is an increasing incidence of co-infections, such as HIV-1 and tuberculosis (TB), in which each disease involves combination therapy (Kwara et al., 2010). Furthermore, the use of herbal/dietary supplements and substances of abuse in many cases, e.g., HIV-1 infec-tion, further complicates CYP-mediated drug interactions (Antoniou and Tseng, 2002; Pal and Mitra, 2006a; Shi and Klotz, 2012). CYP-mediated drug interactions mainly occur as a result of induction or inhibition of CYP enzymes by these agents, as well as due to the presence of CYP single nucleotide polymorphism (SNP) in many ethnic populations (Fig. 18.1) (McGraw and Waller, 2012; Zhou, 2008). (a)

18.3.1 CYP InductionThe induction of CYP enzymes by agents, including drugs, increases the levels of CYP enzymes, which accelerates the metabolism of drugs (e.g., drug A) (Fig. 18.1). Thus, simultaneous use of an inducer drug (e.g., drug B) with drug A increases the metabolism of drug A, which in turn decreases the bioavailability and efficacy of drug A (Fig. 18.1). Since an increased metabolism of drug A is expected to rapidly produce drug metabolite(s), which could be toxic, it is expected to increase drug toxicity. On the other hand, with regard to prodrugs, which are activated into pharmacologically active drugs by CYP enzymes, the CYP induction by drug B would increase the bioavailability and efficacy of prodrugs. However, this would also increase toxicity because the activated drugs are generally toxic at high dose. Thus, to acquire an appropriate therapeutic effect and minimal toxicity the dose of drug A or prodrug needs to be optimized.