Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction

Abstract

This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction. Patients and Methods: Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software. Results: Compared with the normal liver function group, the plasma elimination half-life (T 1/2 ) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (V d ) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T 1/2 , and weight associated with area under the curve (AUC (0→∞) ) independently. Conclusion:The T 1/2 , mean residence time, and V d of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.

Population pharmacokinetics of nalbuphine in patients undergoing general anesthesia surgery

“…The typical values of nalbuphine PK parameters from the final model were 32.9 L/h for CL, 32.5 L for V1, 245 L/h for Q and 83.5 L for V2. The results were consistent with our previous results, which were obtained using non-compartmental analysis (NCA) ( Gao et al, 2022 ). While Bressolle et al (2011) built a PopPK model of nalbuphine after surgery in children (1–11 years) using an allometric scaling model, and their population parameter estimates were 130 L/h/70 kg for CL, 210 L/70 kgforV1, 75.6 L/70 kg for Q and 151 L/70 kg for V2.…”

“… Sear et al (1987) found that nalbuphine exhibited lower total clearance (CL) and apparent volume of distribution (V d ) in anesthetized patients compared with the results obtained in awake volunteers. Similarly, our previous study ( Gao et al, 2022 ) found that nalbuphine CL(33.42 L/h) and V d (137.69 L) were significantly lower in patients undergoing general anesthesia than in healthy patients (CL 90.0 L/h; V d 326.5 L) ( He et al, 2021 ), regardless of whether the patient had liver dysfunction. However, neither of these studies analyzed the reasons for the above-mentioned results.…”

“…In addition, adult patients with liver disease belong to a special population whose metabolism of drugs is different from that of healthy adults. Hepatic insufficiency could alter the drug distribution and metabolic processes by affecting drug metabolizing enzyme activity, hepatic blood flow and drug binding to plasma proteins ( Gao et al, 2022 ). Nalbuphine is mainly metabolized in the liver mainly by cytochrome P450 enzymes (CYP450) 3A4, 2D6, 2C19 and uridine diphosphate-glucuronyl transferase (UGT) 1A3, 2B7, and clearance is mainly dependent on hepatic blood flow ( Bressolle et al, 2011 ).…”

“…Nalbuphine is mainly metabolized in the liver mainly by cytochrome P450 enzymes (CYP450) 3A4, 2D6, 2C19 and uridine diphosphate-glucuronyl transferase (UGT) 1A3, 2B7, and clearance is mainly dependent on hepatic blood flow ( Bressolle et al, 2011 ). Our previous NCA analysis found that the t 1/2 of nalbuphine in patients with hepatic insufficiency was prolonged with increased serum total bilirubin (TBIL) levels ( Gao et al, 2022 ). Although 55.6% of the patients in this study had hepatobiliary disease, there were no covariates related to liver function that could be included in the final model.…”

“…The lower limit of quantitation (LLOQ) was 0.1 ng/mL. The calibration range was 0.1–500 ng/mL ( Gao et al, 2022 ).…”