Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects

Abstract

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR-RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4 mgkg(-1)). The plasma concentrations of cyclosporine were measured for up to 24 h post dose by high-performance liquid chromatography-electrospray mass spectrometry. We found that the mean Cmax (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng ml(-1) (*18B/*18B)(p = 0.037) and the mean AUCO-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml(-1) h (*18B/*18B) (p=0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, Tmax exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2 h post dose compared with *1/*18B (p = 0.062) or *1/*1 (p = 0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p > 0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.

Effect of CYP3A4*18B polymorphisms and interactions with OPRM1 A118G on postoperative fentanyl requirements in patients undergoing radical gastrectomy

“…The CYP3A4*18B polymorphism was identified to be associated with significant variability in fentanyl consumption 48 h following radical gastrectomy in Chinese Han patients. This polymorphism was previously found at high frequencies in Asian populations (9,10). The CYP3A4*18B mutant allele frequency is 28.4% in patients of this study, consistent with previous reports of 24.9% in 416 Japanese individuals (9), 22.7% in 176 Chinese patients undergoing lower abdominal surgery (11) and 26.9% in 143 Chinese gynecological patients (12).…”

“…This discrepancy may, in part, be explained by variations in surgery types (upper vs. lower abdominal surgery), small sample size [97 (present study) and 79 (22) vs. 176 (11) and 143 (12) patients], analgesic formula [fentanyl only vs. fentanyl + droperidol (11,12)] and additional unknown factors. By contrast, Hu et al (10) reported that the CYP3A4*18B genotype significantly affects cyclosporine pharmacokinetics and is likely to result from higher enzymatic activity associated with this mutation. Results of both previous studies and the present study indicate that the CYP3A4*18B variant allele may be critical for polymorphic CYP3A4 enzymatic activities and thus variations in the consumption of fentanyl.…”

“…A number of factors, including the character and intensity of external pain stimuli, age, gender, weight and genetic variation, may affect analgesic requirements. Among these, the contribution of variations in the CYP3A4 and OPRM1 genes has attracted considerable attention (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)24). The CYP3A4*18B polymorphism was identified to be associated with significant variability in fentanyl consumption 48 h following radical gastrectomy in Chinese Han patients.…”

“…Forty single nucleotide polymorphisms (SNPs) of CYP3A4 alleles have been identified. CYP3A4*18B, a SNP in intron 10 of the CYP3A4 gene, was initially identified in Japanese patients and is present at high frequency in Asian populations (9,10). This SNP creates a G→A substitution at position 82,266, which correlates with increased CYP3A4 enzymatic activity (9,10).…”

Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients

“…A series of studies examined the relationship between the CYP3A4*1G polymorphism and drug metabolism but resulted in inconsistent findings [32][33][34] . In agreement with our observation, CYP3A4*1G was not associated with cyclosporine concentrations in 126 renal recipients [27] ; however, Qiu et al [22] and Hu et al [35] found that it was associated with a lower CsA concentration. Differences in study populations, sample size, ethnicities and particularly in the duration after transplantation might be possible confounding factors.…”