Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

Abstract

The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32-1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK-PD relationship best. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.Recently, the pharmacokinetic-pharmacodynamic (PK-PD) relationship of buprenorphine for the effect on the respiratory response has been studied in rats and humans (Yassen et al., 2007). In these investigations, buprenorphine has been shown to display ceiling of the respiratory depressant effect, indicating that buprenorphine acts functionally as a partial agonist at the -opioid receptor. The in vivo behavior correlates well with data obtained from in vitro receptor binding assays (Martin et al., 1976;Lee et al., 1999;Lutfy et al., 2003). Clearly, partial agonistic activity for respiratory depression contributes to the safety profile on buprenorphine administration even at high doses .In the previous investigations, the observed hysteresis between plasma concentration and effect has in part been explained by slow receptor association and dissociation kinetics at the -opioid receptor. This pharmacological characteristic is unique for buprenorphine and is not shared by other opiates like morphine and fentanyl (Cowan et al., 1977;Boas and Villiger, 1985). The slow receptor association-dissociation kinetics may be a complicating factor in the reversal of buprenorphine-induced respiratory depression with naloxone. Furthermore, buprenorphine was shown to bind with high affinity to the -opioid receptor. Specifically, the estimate of the equilibrium d...

Buprenorphine and norbuprenorphine findings in hair during constant maintenance dosage

“…Nonetheless, the observation that the mean steady-state concentration of NBUP in blood often exceeds the concentration of BUP following chronic sublingual administration in humans may account for the present findings [3,8]. Not only the elimination half-life of the metabolite is longer than that of the parent drug but also its rate of elimination has been shown to decrease with increasing blood concentration [9]. However, caution is advisable extrapolating the present data to a single or occasional use of BUP.…”

Buprenorphine May Not Be as Safe as You Think: A Pediatric Fatality From Unintentional Exposure

“…21 Results from several small studies suggest that unlike full m-agonists, such as methadone, excessive dosing of the partial m-agonist buprenorphine may be safe because of the ceiling effect in respiratory depression. 2,3,14,22 In 1 study, increasing the dose of buprenorphine (range: 0.05 to 0.60 mg) decreased the minute ventilation of healthy adult volunteers by 50% from the baseline; administration of higher doses did not cause further respiratory depression. In contrast, fentanyl caused dose-dependent respiratory depression and apnea.…”

“…1 Buprenorphine has the theoretical advantage of having a "ceiling effect" on its ability to produce respiratory depression. [2][3][4][5] Moreover, unlike methadone maintenance programs that require daily, supervised visits and dispensing by a federally certified clinic, buprenorphine/naloxone is prescribed by certified physicians for unsupervised use outside of a health care facility.…”

P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception

“…A plausible hypothesis for the profound norbuprenorphine effect despite such low brain concentrations is high respiratory depressant potency. Although norbuprenorphine potency has been modeled in silico (Yassen et al, 2007), potency of norbuprenorphine respiratory depression remains to be elucidated in vivo. Furthermore, the receptor type involved in mediating norbuprenorphine-induced respiratory depression is still unresolved.…”