Psychotropic medications and cytochrome P450 2D6 pharmacokinetic considerations in the elderly

Background: The genetically polymorphic cytochrome P450 2D6 isozyme (CYP2D6) is responsible for the metabolism of numerous psychotropic medications pertinent to the practice of geriatric psychiatry. Optimal use of psychotropics in the elderly requires a thorough understanding of the determinants of marked variability in plasma concentrations. This review article will focus on basic pharmacokinetic considerations for elderly patients when psychotropics metabolized by CYP2D6, such as nortriptyline and desipramine, are prescribed. Method: A MEDLINE search was conducted using the subject headings ''cytochrome P450,'' ''pharmacokinetics,'' and psychotropics. '' Relevant articles from bibliographies were also collected. Results: CYP2D6 activity does not change with age. Approximately 5% to 10% of whites are poor metabolizers for CYP2D6 and are at risk for drug toxicity. Among Asians, although the prevalence of poor metabolizers is only 1%, the distribution of CYP2D6 activity in extensive metabolizers is shifted toward lower values relative to whites. CYP2D6 activity may be impaired by inhibitors such as paroxetine at fluoxetine. Inhibition of CYP2D6 activity may result in nonlinear plasma drug concentration kinetics, as well as kinetic drug interactions when other drugs metabolized by CYP2D6 are coadministered. Among extensive metabolizers, there is considerable interindividual variation in CYP2D6 activity. Significant correlations have been reported between individual CYP2D6 activity and plasma concentrations of nortriptyline and desipramine. Conclusion: Clinical measurement of CYP2D6 activity may potentially assist in prediction of doses required to achieve therapeutic plasma concentrations of psychotropics metabolized by CYP2D6 in individual patients. Although CYP2D6 activity does not change with age, the pharmacokinetics of psychotropics metabolized by CYP2D6 may change because of age-associated changes in hepatic bloodflow, volume of distribution, and renal elimination of metabolites.