Prior to entering the systemic circulation, drugs and xenobiotics are subject to preabsorptive and first-pass metabolism. This is often a significant limitation to the delivery of drugs via the oral route.1,2 Although problems with drug stability and dissolution can sometimes be addressed with formulation approaches, it is difficult to use these approaches to significantly alter delivery of drugs that are subject to metabolism. Drugs that have low bioavailability (%F) due to high preabsorptive and first-pass metabolism are likely to have a high degree of inter- and intrapatient variability3 and are more likely to suffer from drug-drug interactions. Also, drugs with low %F are likely to require suboptimal dosing regimes, i.e., b.i.d. or t.i.d., and/or relatively high doses. The former leads to poor patient compliance, suboptimal efficacy, and marketing issues, and the latter may lead to unanticipated toxicities due to a large flux of drug and drug metabolites. An additional consideration is the fact that interspecies differences in metabolic enzyme systems will make the prediction of human absorption, distribution, metabolism, and excretion (ADME) properties much more challenging than for drugs cleared via direct elimination.

These considerations make it important to understand the preabsorptive and first-pass metabolism characteristics of candidate drug molecules and to optimize these characteristics preclinically when possible. Drug metabolism plays a central role in modern drug discovery and candidate optimization, recent reviews have detailed how metabolism has impacted the discovery process and challenges that the field faces in the future.4-8

The special case of prodrugs requires an even greater understanding of the metabolism characteristics because of the delicate balance between preabsorptive stability and postabsorptive instability that must be achieved. Also, the potential for prodrugs to be metabolized by pathways not leading to direct bioactivation must be considered.

This chapter will review the enzyme systems responsible for preabsorptive and first-pass metabolism in the intestine and liver. Also covered are methods to study the effects of these enzyme systems in vitro and in vivo.

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