Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing

Aims The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and af ter increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18-45 years, CYP2D6 extensive metab olizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after break fast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dos e was increased to 90 mg twice daily for 3 days, the final dose of 120 mg w as administered twice daily for 3 days (multiple dose: m.d.). Blood samplin g and urine collection: during 60 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of bot h, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,infinity)) and during steady-state doses of 60 mg DHC (AUC(0,12 h)). Du ring increasing steady-state doses of DHC, the data showed a dose linearity of AUG, maximal serum concentration (C-max) and minimal steady-state serum levels (C(ss)min) of both, DHC and DHM (P<0.0001), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (60 mg: 0.989 ; 90%CI 0.951-1.028, 90 mg: 0.997; 90%CI 0.959-1.036, 120 mg: 0.977; 90%CI 0.940-1.016). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CY P2D6. Conclusions In the studied dose range (60-120 mg) the pharmacokinetics of D HC and its active metabolite DHM are linear in EMs of CYP2D6.