Pharmacokinetics of morphine and its surrogates VI: Bioanalysis, solvolysis kinetics, solubility, pK'a values, and protein binding of buprenorphine.
The 10-fold greater sensitivity of buprenorphine to fluorescence compared with morphine provides excellent detection for HPLC assay of buprenorphine in biological fluids with a 5-ng/mL sensitivity. Buprenorphine yields a stoichiometric final acid degradation product, a fluorescent-detectable, rearranged demethoxy analogue of buprenorphine, which serves as an excellent bioassay internal standard. Buprenorphine solvolysis is specific-acid and specific-base catalyzed. Alkaline hydrolysis produces no fluorescent products. Acid hydrolysis also produces a fluorescent-detectable, transient dehydro intermediate that is also completely transformed to the demethoxy analogue. The rate constants and Arrhenius parameters for these transformations have been determined. Estimated buprenorphine pK'a values are 8.24 and 10 for the ammonium and phenol groups, respectively. The intrinsic aqueous solubility of neutral buprenorphine is 12.7 +/- 1.2 micrograms/mL at 23 degrees C. The red blood cell-plasma water partition coefficients of buprenorphine ranged between 6 and 15. Ultracentrifugation and the red blood cell partition methods led to an estimated 95-98% plasma protein binding. Ultrafiltration and equilibrium dialysis methods were inappropriate because of the high membrane binding of neutral buprenorphine.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002047:Buprenorphine / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009019:Morphinans / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism*; D011485:Protein Binding; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013696:Temperature; D014461:Ultracentrifugation
D001798:Blood Proteins; D009019:Morphinans; D002047:Buprenorphine; D009020:Morphine