Effect of cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Abstract

Amlodipine is a racemic mixture composed of S- and R-form and metabolized stereoselectively. Cytochrome P450 3A (CYP3A) including CYP3A5 are involved in the metabolism of amlodipine and it was reported that polymorphic CYP3A5 genotype modulates the plasma levels of amlodipine and thus affect its pharmacokinetics. This study was conducted to find whether stereoselective pharmacokinetics of amlodipine was affected by the polymorphic CYP3A5 genotype. Seventeen healthy subjects were genotyped for CYP3A5*3 variant. After a single dose of 10-mg amlodipine, enantiomers of amlodipine were analyzed using HPLC-MS/MS equipped with an AGP column. Amlodipine showed stereoselective pharmacokinetics. S-amlodipine exhibited higher plasma levels than R-amlodipine in both genotype groups. S-amlodipine showed 15% higher mean peak plasma concentrations (Cmax) in CYP3A5*1/*3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P = 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P = 0.114). CYP3A5*1/*3 carriers also have 23 and 12% higher mean area under the time versus concentration curve of R-amlodipine and S-amlodipine than CYP3A5*3/*3 carriers, respectively (for R-amlodipine, 147.1 ng*h/ml for CYP3A5*1/*3 carriers versus 121.8 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.234; for S-amlodipine, 161.6 ng*h/ml for CYP3A5*1/*3 carriers vs. 144.2 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.353). Other pharmacokinetic parameters also showed no significant difference between them. In conclusion, the present study showed that despite the evidence that amlodipine is stereoselectively metabolized, CYP3A5*3 genotype did not affect stereoselective disposition of amlodipine. It provides the evidence that CYP3A5*3genotype plays a minor role in the interindividual variability of stereoselective disposition of amlodipine in humans.

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

“…It has been demonstrated that people with at least one CYP3A5*1 allele express large amounts of enzyme, while the single-nucleotide polymorphisms in CYP3A5*3 and *6 exhibit alternative splicing and protein truncation. Consequently, those with CYP3A5*3 genotype have variable drug metabolism compared with the CYP3A5*1 populace (Kim et al, 2009). It is likely that those with CYP3A5*3 or *6 would have decreased metabolism of GCs, and therefore higher levels of GCs at the therapeutic site of action.…”

Comparing Antihypertensive Effect and Plasma Ciclosporin Concentration between Amlodipine and Valsartan Regimens in Hypertensive Renal Transplant Patients Receiving Ciclosporin Therapy

“…[36] The presence of a CYP3A5*3 allele causes a splicing defect, resulting in a loss of enzymatic activity. [37][38][39] In the current study, we have shown that patients with the CYP3A5*3*3 genotype displayed more reduction in DBP when they were treated with amlodipine but not with valsartan (see table II). Meanwhile, the plasma ciclosporin concentration was elevated in those patients with CYP3A5*3*3 genotype and treated with amlodipine but not valsartan (see table II).…”

Pharmacokinetic and haemodynamic interactions between amlodipine and losartan in human beings

“…It is rapidly absorbed with relatively high absolute bioavailability (approximately 64%) following oral administration owing to its low hepatic extraction ratio . It is a known substrate of cytochrome P450 (CYP) 3A …”

“…Although co‐administration of amlodipine and losartan might be an attractive treatment option with better clinical outcomes, the potential that pharmacokinetic interactions resulting in elevation of blood drug levels might be responsible for the beneficial effects of the combination cannot be ruled out. It was hypothesized that possible interactions between amlodipine and losartan might be attributed to a common metabolic pathway via CYP3A4 …”