- Understand important intrinsic and extrinsic nongenetic factors that can affect phase I and phase II drug metabolism.
- Be able to identify and recognize clinically important metabolism-based interactions.
- Understand the mechanisms of CYP inhibition and induction.
The main goal of successful drug therapy is to ensure that a patient receives safe and effective drug treatment. Therapeutic drug concentrations need to be achieved to accomplish this goal. A solid understanding of the factors that can affect drug disposition is critical in achieving appropriate drug concentrations (Figure 8–1). Drug dose or dosing frequency may need to be modified according to changes in drug biotransformation or excretion caused by intrinsic or extrinsic factors. In this chapter, intrinsic and extrinsic factors known to affect metabolism, with a particular focus on cytochromes P450 (a principal component of drug-metabolizing enzymes), will be discussed.
Intrinsic and extrinsic factors can influence the pharmacokinetics of a drug. The changes in drug clearance that occur can result in subtherapeutic, therapeutic, or supratherapeutic drug concentrations that in turn can lead to optimal drug effect or undesired drug effects.
A plethora of research focuses on age-based differences in drug metabolism. In pediatric patients, changes in the ontogeny of drug-metabolizing enzymes account for many of the differences in drug disposition between children and adults. Studies show differential expression patterns of CYP enzymes in neonates, infants, children, and adolescents.1 Developmental changes such as changes in gastric acid production, gastric emptying, renal function, pancreatic function, body composition, and total body water also play a role in the evolving absorption, distribution, metabolism, and excretion processes in infants and children. These developmental changes contribute to variability in drug disposition in the pediatric population.2
On the other side of the age spectrum are the elderly, who are generally described as those aged 65 years or older. In the elderly population, the aging process may involve a progressive decrease in organ and tissue function (in particular, the kidney) that can lead to altered drug disposition. Although liver size and hepatic blood flow generally decrease with age, routine clinical tests of liver function reveal that hepatic function does not change significantly.3 In addition, in vitro studies investigating CYP enzyme activity in human hepatocytes find no differences in the activities of the 10 most predominant CYP isoforms between the age groups of 20–60 and above 60 years.4 In clinical studies, the effect of age on CYP enzymes appears to be isoform-dependent. Plasma paroxetine concentrations were evaluated in depressed patients aged 69–95 years and no age-related changes in paroxetine disposition (metabolized by CYP2D6) were detected.5 In studies involving the clearance of antipyrine (metabolized by CYP3A4 and CYP3A5 [collectively referred to as “CYP3A4/5” due to their high degree of homology and function], CYP1A2,CYP2C8, and CYP2C9), an approximate 20–25% decline ...