Genotype and phenotype of cytochrome P450 2D6 in human immunodeficiency virus-positive patients and patients with acquired immunodeficiency syndrome

Abstract

Objective: To examine the distribution of the cytochrome P ₄₅₀ (CYP) CYP2D6 phenotype and its relation to genotype, concomitant medication, and disease state in human immunodeficiency virus (HIV)-positive patients.

Design: A cross sectional study with a longitudinal component compared individual genotypes for CYP2D6 to the CYP2D6 phenotype.

Methods: Sixty-one predominately male Caucasian, HIV-positive patients were recruited and CYP2D6 genotypes [extensive metabolizer (EM) or poor metabolizer (PM)] determined by polymerase chain reaction (PCR)-based amplification, followed by restriction fragment-length analysis. The patients were also phenotyped using dextromethorphan (DM) to determine their respective enzyme activity and assigned either a CYP2D6 EM or PM phenotype. Complete medical and treatment histories were compiled. A total of 44 patients were tested longitudinally.

Results: Fifty-nine patients (97%) possessed an EM genotype, consistent with previously observed distributions in demographically similar populations. In healthy seronegative populations, genotype and phenotype have been shown to be essentially interchangeable measures of CYP2D6 activity. In this cohort, 2 of the 59 patients with an EM genotype expressed a PM phenotype. In addition, 4 EM patients were less extensive DM metabolizers than any of the patients receiving medication known to inhibit CYP2D6. This apparent shift toward the PM phenotype from the EM genotype was associated with the presence of active illness.

Conclusion: Changes may occur in HIV-positive patients such that their CYP2D6 activity approaches that of PMs, despite having an EM genotype. Neither active disease nor drug interactions alone explain the shift.