Mutation types of CYP3A enzymes and sex differences in sufentanil metabolism

To explore the sex differences in drug metabolism of sufentanil in Chinese patients based on the mutation classification of cytochrome P450 3A (CYP3A) enzymes.

According to the possible effects of combined cytochrome P450 3A4 gene*1G locus (CYP3A4*1G) and cytochrome P450 3A5 gene*3 locus (CYP3A5*3) mutation groups on Chinese population, we added different weights to CYP3A4*1G and CYP3A5*3 polymorphisms and classified patients into 3 groups: Group Ⅰ, patients carried either the CYP3A4*1G/*1G allele or both CYP3A4*1/*1G allele and CYP3A5*3/*3 allele; Group Ⅱ, patients with both CYP3A4*1/*1G allele and CYP3A5*1/*3 allele; Group Ⅲ, patients with either the CYP3A4*1/*1 allele or both CYP3A4*1/*1G allele and CYP3A5*1/*1 allele. A single-dose, double-blind, stratified random sampling was performed, and 255 patients undergoing endoscopic surgery in the First Affiliated Hospital of Army Medical University were finally subjected. According to the results of genetic testing, an independent statistician, before operation, randomly selected 30 patients from each stratified group to form a study cohort (male-female ratio of 1∶1) and named each group A, B or C. Clinical investigators and subjects kept double-blind to the results of grouping and genetic testing. After entering the operating room, the subjected 90 patients received a single dose of sufentanil followed by collection of blood samples at 10 time points including 2 min before and from 2 to 120 min after administration. After the surgery, we determined the plasma drug concentration, calculated the pharmacokinetic parameters, and compared the metabolic differences between different genders in each group and unblinded the study.

The cohort best fitted the two-compartment pharmacokinetic model, and groups A, B and C corresponded to group Ⅰ, Ⅱ and Ⅲ, respectively. In different patient groups based on mutatron types of CYP3A enzymes the females had lower plasma drug concentration-time curves at each time point, higher systemic clearance (P≤0.01) and smaller area under the plasma concentration-time curve from zero to infinity (P<0.05) when compared with the males. In addition, in group Ⅰ, the elimination rate of central compartment and movement rate of drug from central compartment to peripheral compartment were obviously greater in the females than the males (P<0.05), while the distribution half-life (P<0.05) and elimination half-life (P<0.01) were notably longer in the males than the females. In both group Ⅱ and group Ⅲ, the males obtained larger total area under the plasma concentration-time curve than the females (P<0.05).

There are sex differences in the drug metabolism of sufentanil in Chinese patients. Women show faster distribution and higher clearance of sufentanil while men present greater drug exposure. Preoperative CYP3A genotyping and intraoperative personalized medication are of great significance to ensure the safety in clinical practice.