Effects of normal body weight and overweight status on metabolism of sufentanil in patients with same CYP3A4/5 genotype: A prospective clinical study

To explore the pharmacokinetic characteristics of sufentanil in individuals with normal body mass index (BMI), overweight BMI, and different CYP3A4/5 enzyme genotypes.

The patients receiving laparoscopic surgery under general anesthesia in the First Affiliated Hospital of Army Medical University from November 2020 to September 2021 were prospectively recruited in this study. Before the operation, the oral swabs were collected from all the patients for genotyping using the human CYP3A4/5 gene kit. Based on the potential impact of combination of their polymorphisms on sufentanil metabolism and the proportion of different genotype combinations of CYP3A4/5 enzymes, the patients were divided into groups Ⅰ (3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation), Ⅱ (3A4 heterozygous mutation + 3A5 heterozygous mutation), and Ⅲ (3A4 wild type or 3A4 heterozygous mutation + 3A5 wild type). According to their BMI, they were also assigned into a normal body weight group (18.5~24.0 kg/m²) and an overweight group (24~<28 kg/m²), and the differences in drug metabolism parameters were statistically analyze between the 2 groups. After routine general anesthesia induction (sufentanil 0.5 μg/kg), venous blood samples were collected to detect the changes in its concentration using high performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetic data of sufentanil were calculated between the normal BMI group and overweight group in all participants and between the 2 body weight groups among those with different genotype combinations.

Among the 90 participants completing the blood drug concentration test, 8 patients had their blood samples contaminated (including 1 case with an anesthesia duration of <2 h), and 3 were excluded due to low weight or overweight. Eventually, 79 participants were included in the pharmacokinetic analysis on the normal body weight group and the overweight group. Compared with the normal body weight group, the central compartment volume of distribution in the overweight group was significantly reduced (p<0.05), while no obvious differences were observed between the 2 groups in terms of peripheral compartment volume of distribution, total clearance rate, peripheral compartment clearance rate, distribution half-life, clearance halflife, and area under the blood concentration-time curve. In group Ⅰ (n=26), the overweight patients (n=13) had significantly reduced central compartment volume of distribution, peripheral compartment volume of distribution, and peripheral compartment clearance rate when compared with the normal body weight patients (n=13) (P<0.05), while no differences were observed in other pharmacokinetic parameters. In groups Ⅱ (n=25) and Ⅲ (n=28), the overweight patients and normal body weight patients had no statistical differences in all pharmacokinetic parameters.

Among the patients with the same genotype combination of CYP3A4/5 mutations, there was no difference in the metabolism of sufentanil between the overweight and normal weight patients. Additionally, in the population of 3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation, the overweight patients have smaller peripheral distribution range of sufentanil, and weakened metabolic process.