| As active drug metabolites may have profound pharmacological and toxicological effects on patients, a thorough understanding of the metabolic fate of the parent drug and the potential pharmacological and toxicological activities of its metabolite(s) is essential to the effective and safe usage of the drug. Thus the objectives of this study were to investigate the metabolic fate of hydromorphone in patient(s) receiving chronic hydromorphone therapy and to test for antinociceptive activities of the metabolites thus identified and synthesized.;Hydromorphone-3-glucuronide, hydromorphone-3-sulfate, dihydromorphine, dihydroisomorphine, dihydromorphine-3-glucuronide, dihydroisomorphine-3--glucuronide and norhydromorphone were isolated from pooled urine samples of a cancer patient receiving chronic hydromorphone therapy. The metabolites were analyzed using a high-performance liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method.;The presence of hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide, and unconjugated dihydromorphine and dihydroisomorphine was confirmed for the first time in pooled urine samples of a human subject. Hydromorphone-3-sulfate, dihydroisomorphine-3-glucuronide and norhydromorphone were novel metabolites of hydromorphone identified for the first time.;LC-MS-MS assays were also developed for the determination of morphine and its metabolites, and hydromorphone and its metabolites in plasma samples of male Sprague Dawley rats.;Following morphine administration, morphine-3-glucuronide was detected as the predominant metabolite of morphine, whereas normorphine was detected as a minor metabolite. The slopes of the apparent elimination phases for morphine-3-glucuronide and morphine were not significantly different, suggesting the elimination rate constant of morphine-3-glucuronide is much greater than that of morphine and the formation of morphine-3-glucuronide is the rate-limiting step for the elimination of this metabolite following morphine administration.;The 3-O-glucuronide metabolites were detected as the common major metabolites following administration of hydromorphone, dihydromorphine and dihydroisomorphine. Norhydromorphone glucuronide was tentatively detected as a major metabolite following norhydromorphone administration.;The antinociceptive activities of hydromorphone, dihydromorphine, dihydroisomorphine and norhydromorphone were determined using the formalin test. Morphine was also tested as a reference standard for comparison of antinociceptive activities between these compounds. (Abstract shortened by UMI.)... |
