In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

Abstract

ABSTRACT:A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t 1/2 of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.Esters have been the most common approach for prodrug development, because ester linkage of prodrugs tends to be converted efficiently to the active species through wide variability of esterase in the organs and tissues (Williams, 1985;Leinweber, 1987). The ester prodrugs apparently show that the safety and pharmacological actions of prodrugs seem to be the same as those for the parent compound (He et al., 1999;Ishikawa, 1999;Noble and Goa, 1999;Doucette and Aoki, 2001;Beaumont et al., 2003;Fischer et al., 2003). Nalbuphine is a potent -receptor agonist, -receptor antagonist analgesic with relatively low side effects (Jasinski and Mansky, 1972;Beaver and Feise, 1978). However, its short elimination half-life results in frequent injections for control of moderate to severe pain in clinical cases (Lo et al., 1987). SDN is a novel synthetic diester prodrug of nalbuphine designed to have high lipophilicity that consequently prolongs the duration of nalbuphine after intramuscular injection (Fig. 1).A successfully designed prodrug should not only be well absorbed, but should also metabolize primarily and readily to its active moiety. The prodrug should fulfill several criteria as proposed by Bodor (1984). Basically, no unexpected compound should be formed in vivo. Red blood cells and plasma are known to contain esterase (Leinweber, 1987;Cossum, 1988). In this study, SDN was examined for i...

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

“…This result showed the very limitedly releasing of SDE from oily solution and very fast de‐esterification to nalbuphine after releasing from the injection site. According to the previous in vitro study reported (Pao et al ., ) evidence indicated that SDE was unstable in blood or plasma and the de‐esterification of SDE rapid within 60 min. This might explain why the SDE could not detect in human plasma after SDE administration.…”

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

“…Previous in vitro metabolism studies in rat, rabbit, dog and human blood (Pao, Hsiong, Hu, Wang, & Ho, ) reported that the conversion of DNS to nalbuphine in whole blood occurred within 2 to 30 min. It is also reported that DNS was rapidly converted to nalbuphine in rats after intravenous administration exhibiting a mono‐exponential decay.…”

Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases

“…Although the pro-soft concept has been discussed previously, there are few working examples and there has been little exploration of their potential. 26 1 is well suited for testing such potential (Figure 1). With three distinct biological activities and six known targets, a wide variety of pro-soft constructs of 1 can be envisaged.…”