Simultaneous determination of nalbuphine and its prodrug sebacoly dinalbuphine ester in human plasma by ultra‐performance liquid chromatography–tandem mass spectrometry and its application to pharmacokinetic study in humans

Abstract

A rapid, simple, sensitive and selective ultraperformance liquid chromatography-tandem spectrometry (UPLC-MS/MS) method for the determination of nalbuphine and its prodrug sebacoly dinalbuphine ester (SDE) was developed and validated in human plasma. The sample pretreatment involves basification and iterative liquid-liquid extraction with ethyl-ether-dichloromethane (7:3, v/v) solution, followed by LC separation and positive electrospray ionization (ESI) API-3000 mass spectrometry detection. The chromatography was on a Waters Acquity UPLC BEH HILIC column (2.1 × 100 mm, 1.7 µm). The mobile phase was composed of acetonitrile and water (83:17, v/v) that contained 0.2% formic acid and 4 mm ammonium formate at a flow rate of 0.25 mL/min. Ethylmorphine and naloxine were selected as the SDE and nalbuphine internal standard (IS), respectively. The calibration curve for both was linear over the range from 0.05 to 20 ng/mL, with correlation coefficients ≥0.995. The lower limit of quantification was set at 0.05 ng/mL. The intra- and inter-day precision values for nalbuphine and SDE were acceptable as per FDA guidelines. The method was applied successfully to determine nalbuphine concentration in human plasma samples obtained from four Taiwanese volunteers receiving intramuscularly administration of sebacoyl dinalbuphine ester. The method is sensitive, selective and directly applicable to human pharmacokinetic studies involving nalbuphine.

Comparison of the Efficacy and Safety of Dinalbuphine Sebacate, Patient-Controlled Analgesia, and Conventional Analgesia After Laparotomy for Gynecologic Cancers: A Retrospective Study

“…Therefore, with a lower maximum blood concentration, DNS has a better safety profile than nalbuphine itself. No opioid antagonism or severe nalbuphine-induced AEs were observed in the DNS group, which may due to the single-dose extended release of DNS resulting in a relatively low maximum plasma concentration of nalbuphine ( C max = 16.8 ng/mL), 30 which led to the lower trend in dizziness, nausea, and vomiting observed in our study. While injection site reactions (ISRs) such erythema and swelling were commonly reported AEs in oil-based IM injection products.…”

Pharmacokinetic comparison of nalbuphine with single injection and patient‐controlled analgesia mimic method in healthy Chinese volunteers

“…Plasma concentrations of nalbuphine were determined by high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS), the details of which were reported in Huang's study 20 . Briefly, the plasma was mixed with nalbuphine‐d 3 (internal standard) and precipitated with acetonitrile (Fisher Technology Inc., USA).…”

Pharmacokinetics of dinalbuphine sebacate and nalbuphine in human after intramuscular injection of dinalbuphine sebacate in an extended‐release formulation

“…It is also reported that DNS was rapidly converted to nalbuphine in rats after intravenous administration exhibiting a mono‐exponential decay. A pilot clinical study demonstrated that when 75 mg of DNS was administered intramuscularly, nalbuphine was the only measurable product, while the plasma concentrations of DNS were below the low quantitation limit (Huang et al, ). There were two points worthy of concern, one was the issue of hydrolysis and the other was DNS lipophilicity.…”