REGULATION OF CYTOCHROME P4503A ACTIVITY IN THE ELDERLY

Tufts University Boston, Boston MA

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Abstract

DESCRIPTION: (Adapted from applicant's abstract) Pharmacologic treatment is an important part of the therapy of mental disorders in the aged population. Central nervous system (CNS) concentrations of these drugs are determined in part by plasma concentrations, which show increasing variability with age. These changes however, may not fully explain the dynamic differences and seemingly increased sensitivity that has been observed in the elderly population. One particularly important class of drugs where decreased clearance in aging individuals has been documented are those that are substrates for the cytochrome P450 3A (CYP3A) subfamily of enzymes. Clinical pharmacologic studies and in vitro studies using human microsomes have not yet established the mechanism of this kinetic variability. Of interest is that a striking number of substrates and inhibitiors of CYP3A enzymes are also substrates and/or inhibitors of P-glycoprotein (P-gp), a multi-drug transport protein encoded by MDR1 (mdr1 a/b in rodents) found in many tissues, including intestine and the blood-brain barrier (bbb). The function of P gp in the intestine and the bbb have not been clearly define, but indications are that drug bioavailibility and elimination as well as CNS permeability to particular substrates may be importantly influenced by the presence and/or activity of this protein. Hence, the cause of the differences in clearance and sensitivities observed when psychotropic CYP3A substrates are administered to the elderly should be examined for both CYP3A and P-gp components. Although in vitro studies using human microsomes have proven invaluable in elucidating metabolic pathways and predicting drug interactions due to inhibition, the variability in the tissue procurement process and clinical situation preceding tissue donation can make it difficult to use the in vitro methodology to isolate the single variable of age and confidently attribute differences in metabolic activity to that factor alone. Consequently, appropriate animal models may be a more reliable system to study the kinetic and dynamic models of aging. Fischer-344 rats have been shown to handle a number of CYP3A substrates in a manner qualitatively similar to humans. Using this experimental system, dynamic, kinetic and molecular information can be simultaneously obtained to evaluate animal age and gender effects on: hepatic and GI CYP3A expression and function, and response to chemical induction; GI and bbb expression of P-gp; and systemic kinetics and CNS dynamic of a CYP3A-substrate benzodiazepine agonist.