Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, CLEARANCE, DISPOSITION, MIDAZOLAM, BLOOD, LIVER, ATP Binding Cassette Transporter, Subfamily B, Member 1, Adult, Aged, Aged, 80 and over, Cohort Studies, Cytochrome P-450 CYP3A, Female, Genotype, Healthy Volunteers, Humans, Immunosuppressive Agents, Kidney, Kidney Transplantation, Male, Midazolam, Middle Aged, Polymorphism, Single Nucleotide, Tacrolimus, clinical pharmacology, cytochrome P450, drug toxicity, metabolite disposition, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio [CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus (DMT) and 31-DMT, respectively; P < 0.001]. There was, however, no relationship between CYP3A4 activity and tacrolimus metabolite/parent ratios. Additional analyses in 16 healthy volunteers showed that dual pharmacological inhibition of CYP3A4 and P-glycoprotein using itraconazole resulted in increased tacrolimus metabolite/parent ratios (+65%, +112%, and 25% for 13-, 15-, and 31-DMT, respectively; P < 0.01). This finding was confirmed in a cohort of nine renal transplant recipients who underwent tacrolimus pharmacokinetic assessments before and during CYP3A4 inhibition (58% increase in overall metabolite/tacrolimus ratio; P = 0.017).