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

被引:15
作者
Ammon, S [1 ]
Hofmann, U [1 ]
Griese, EU [1 ]
Gugeler, N [1 ]
Mikus, G [1 ]
机构
[1] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70341 Stuttgart, Germany
关键词
dihydrocodeine; dihydromorphine; multiple dose; pharmacokinetics; single dose;
D O I
10.1046/j.1365-2125.1999.00042.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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,infinity)) 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 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 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.
引用
收藏
页码:317 / 322
页数:6
相关论文
共 20 条
[1]   DISPOSITION AND METABOLISM OF CODEINE AFTER SINGLE AND CHRONIC DOSES IN ONE POOR AND 7 EXTENSIVE METABOLIZERS [J].
CHEN, ZR ;
SOMOGYI, AA ;
REYNOLDS, G ;
BOCHNER, F .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1991, 31 (04) :381-390
[2]  
CHEN ZR, 1988, LANCET, V2, P914
[3]   THE EFFECT OF AGING ON THE PHARMACOKINETICS OF DIHYDROCODEINE [J].
DAVIES, KN ;
CASTLEDEN, CM ;
MCBURNEY, A ;
JAGGER, C .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1989, 37 (04) :375-379
[4]   BIOACTIVATION OF THE NARCOTIC DRUG CODEINE IN HUMAN-LIVER IS MEDIATED BY THE POLYMORPHIC MONOOXYGENASE CATALYZING DEBRISOQUINE 4-HYDROXYLATION (CYTOCHROME-P-450 DBL/BUFI) [J].
DAYER, P ;
DESMEULES, J ;
LEEMANN, T ;
STRIBERNI, R .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 152 (01) :411-416
[5]   Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation [J].
Eckhardt, K ;
Li, SX ;
Ammon, S ;
Schänzle, G ;
Mikus, G ;
Eichelbaum, M .
PAIN, 1998, 76 (1-2) :27-33
[6]   POLYMORPHIC OXIDATION OF SPARTEINE AND DEBRISOQUINE - RELATED PHARMACOGENETIC ENTITIES [J].
EICHELBAUM, M ;
BERTILSSON, L ;
SAWE, J ;
ZEKORN, C .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1982, 31 (02) :184-186
[7]   DIHYDROCODEINE - A NEW OPIOID SUBSTRATE FOR THE POLYMORPHIC CYP2D6 IN HUMANS [J].
FROMM, MF ;
HOFMANN, U ;
GRIESE, EU ;
MIKUS, G .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1995, 58 (04) :374-382
[8]   Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population [J].
Griese, EU ;
Zanger, UM ;
Brudermanns, U ;
Gaedigk, A ;
Mikus, G ;
Morike, K ;
Stuven, T ;
Eichelbaum, M .
PHARMACOGENETICS, 1998, 8 (01) :15-26
[9]   SIMULTANEOUS DETERMINATION OF DIHYDROCODEINE AND DIHYDROMORPHINE IN SERUM BY GAS-CHROMATOGRAPHY TANDEM MASS-SPECTROMETRY [J].
HOFMANN, U ;
FROMM, MF ;
JOHNSON, S ;
MIKUS, G .
JOURNAL OF CHROMATOGRAPHY B-BIOMEDICAL APPLICATIONS, 1995, 663 (01) :59-65
[10]   Characterization of the human cytochrome P458 enzymes involved in the metabolism of dihydrocodeine [J].
Kirkwood, LC ;
Nation, RL ;
Somogyi, AA .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1997, 44 (06) :549-555