Although the pharmacokinetics of oral
hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not available regarding the disposition of
hydromorphone and its principal metabolite,
hydromorphone-3-glucuronide (H3G), at steady-state and after large oral doses. The authors studied the pharmacokinetics of
hydromorphone and H3G after
oral administration of an immediate-release (IR) and controlled-release (CR) formulation of
hydromorphone at a daily dose of 48 +/- 11 mg (range 6-216 mg) in a randomized, double-blind, steady-state, two-way crossover evaluation in 18 patients with chronic
cancer pain. Controlled-release
hydromorphone demonstrated equivalent bioavailability and acceptable CR characteristics, when compared with IR
hydromorphone (CR vs. IR: AUC0-12 123.10 +/- 20.38 vs. 118.98 +/- 20.92 ng.hr.mL-1, P = NS, Cmax 17.76 +/- 3.07 vs. 19.70 +/- 4.04 ng.mL-1, P = NS, Cmin 6.04 +/- 1.01 vs. 5.28 +/- 1.000 ng.mL-1, P = NS, and Tmax 4.78 +/- 0.78 vs. 1.47 +/- 0.22 hr, P = 0.0008). A significant linear relationship existed between
hydromorphone dose and
hydromorphone AUC (r = 0.8315, P = 0.0001) and between
hydromorphone AUC and H3G AUC (r = 0.8048, P = 0.0001) over a wide dose range. The steady-state molar ratio of H3G to
hydromorphone was 27:1. The authors conclude that CR
hydromorphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral
hydromorphone is extensively metabolized to H3G, although the pharmacologic activity of this metabolite remains unknown.