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Keywords:

  • Buprenorphine;
  • Pharmacokinetics;
  • Metabolites;
  • Bile cannulated

Abstract

Specific and sensitive reverse-phase HPLC assays of buprenorphine and its metabolite in biological fluids were developed with sensitivities of 2–6 ngml−1 using fluorimetric detection. Pharmacokinetics were monitored on acute bolus administration of buprenorphine in 6 dogs within the 0.7–2.6 mg kg−1 dose range. Toxicity was circumvented when terminal plasma concentrations were increased by infusing 3.7–4.8mg kg−1 doses of buprenorphine over 3 h in six studies in 6 dogs. The terminal rate constants of the IV infusion studies from the triexponential fits of plasma concentration–time data averaged 41.6 ± 7.5 h with an averaged total body clearance of 191 ± 19ml min−1. This terminal rate constant was in contrast to the < 100 min half-life of the second exponential fitting of the less lipophilic morphine, naloxone, and naltrexone. The apparent volumes of distribution of buprenorphine, referenced to the total plasma concentration, were 33 ± 6 1 (Vc, central compartment volume) and 663 ± 891 (Vd, total body volume), indicative of a highly bound, sequestered or lipophilic drug. Unchanged buprenorphine was insignificantly renally (<0.2 per cent of the dose) and biliary (<0.6 per cent) excreted. The major route of buprenorphine disposition was by hepatic conjugation to glucuronide which was eliminated into the bile (about 92 per cent) with only small amounts appearing in urine (< 1 per cent as metabolite). Minor metabolites excreted in the bile accounted for about 3 per cent of the administered dose. Direct IV administration of the metabolite, buprenorphine glucuronide, gave a terminal half-life of 6 h and more than 90 per cent of the systemically circulating metabolite was excreted in bile; only 10 per cent in urine. The oral bioavailability, estimated from the areas under the buprenorphine plasma concentration–time curve following IV and oral administration of buprenorphine in the dogs, was 3–6 per cent. There were no apparent correlations of the buprenorphine time course with cardiovascular parameters such as heart rate, ECG, and blood pressure. Miotic effect was significant. Respiratory depression was observed during the first 4 h after IV bolus injection, but not during the infusion studies.