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 after increasing doses of DHC at steady‐state.

Methods Twelve healthy male volunteers (18–45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after breakfast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dose was increased to 90 mg twice daily for 3 days, the final dose of 120 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling 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 both, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,∞)) and during steady‐state doses of 60 mg DHC (AUC(0,12 h)). During increasing steady‐state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (C_max ) and minimal steady‐state serum levels (C_ssmin) 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 CYP2D6.

Conclusions In the studied dose range (60–120 mg) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6.

DOI: 10.1046/j.1365-2125.1999.00042.x

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