RESUMEN
AIMS: Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic and visceral pain thresholds in extensive and quinidine-induced poor metabolizers. METHODS: Eleven healthy subjects participated in a double-blind, randomized, placebo-controlled, four-way cross-over study comparing the effects of single doses of placebo and slow-release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured. RESULTS: In quinidine-induced poor metabolizers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P < 0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased from 0.91% to 0.28% of the dihydrocodeine dose (P < 0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P < 0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P < 0.05). CONCLUSIONS: In quinidine-induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.
Asunto(s)
Analgésicos Opioides/farmacología , Codeína/análogos & derivados , Dihidromorfina/farmacología , Adulto , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacocinética , Codeína/metabolismo , Codeína/farmacocinética , Codeína/farmacología , Estudios Cruzados , Dihidromorfina/metabolismo , Dihidromorfina/farmacocinética , Método Doble Ciego , Estimulación Eléctrica , Humanos , Masculino , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Quinidina/farmacología , Fenómenos Fisiológicos de la Piel/efectos de los fármacosRESUMEN
The genetic polymorphism of dihydrocodeine O-demethylation in man via analysis of urinary dihydrocodeine (DHC) and dihydromorphine (DHM) by micellar electrokinetic capillary chromatography is described. Ten healthy subjects which are known to be extensive metabolizers for debrisoquine ingested 60 mg of DHC and collected their 0-12 h urines. In these samples, about 1% of the administered DHC equivalents are shown to be excreted as DHM. Premedication of 50 mg quinidine sulfate to the same subjects is demonstrated to significantly reduce (3-4 fold) the amount of O-demethylation of DHC, a metabolic step which is thereby demonstrated to co-segregate with the hydroxylation of debrisoquine. Thus, in analogy to codeine and other substrates, extensive and poor metabolizer phenotypes for DHC can be distinguished. Using the urinary DHC/DHM metabolic ratio to characterize the extent of O-demethylation, the metabolic ratio ranges of extensive and poor metabolizers in a frequency histogram are shown to partially overlap. Thus, classification of borderline values is not unequivocal and DHC should therefore not be employed for routine pharmacogenetic screening purposes. Nevertheless, the method is valuable for metabolic research and preliminary data demonstrate that the same assay could also be used to explore the metabolism of codeine.
Asunto(s)
Codeína/análogos & derivados , Dihidromorfina/orina , Electroforesis Capilar/métodos , Polimorfismo Genético , Codeína/farmacocinética , Codeína/orina , Humanos , Metilación , Micelas , Fenotipo , Quinidina/química , Valores de ReferenciaRESUMEN
After single-dose administration of 40 or 60 mg of dihydrocodeine (DHC, in a slow-release tablet) to four healthy individuals known to be extensive metabolizers of debrisoquine, the urinary excretion of DHC and its four major metabolites, dihydrocodeine-6-glucuronide, nordihydrocodeine, dihydromorphine and nordihydromorphine, was assessed using micellar electrokinetic capillary chromatography (MECC). DHC and two of its metabolites (dihydrocodeine-6-glucuronide and nordihydrocodeine) could be analyzed by direct urine injection, whereas the metabolic pattern was obtained by copolymeric bonded-phase extraction of the solutes from both plain and hydrolyzed urine specimens prior to analysis. The total DHC equivalents excreted within 8 and 24 h were determined to be 30.4 +/- 7.7% (n = 5) and 63.8 +/- 6.1% (n = 2), respectively, and only about 4% of the excreted DHC equivalents were identified as morphinoids. Furthermore, almost no morphinoid metabolites of DHC could be found after administration of quinidine (200 mg of quinidine sulfate) 2 h prior to DHC intake.
Asunto(s)
Cromatografía Liquida/métodos , Codeína/análogos & derivados , Codeína/metabolismo , Codeína/orina , Interacciones Farmacológicas , Electroquímica , Humanos , Hidrólisis , Fenotipo , Premedicación , Quinidina/administración & dosificación , Valores de ReferenciaRESUMEN
Phenotypes for hydroxylation can be predicted by using mephenytoin and dextromethorphan as substrates, whereas phenotypes for acetylation can be determined with caffeine as probe drug. After single-dose administration of one of these drugs, of two of them simultaneously, or of the three drugs together, the major urinary metabolites (4-hydroxymephenytoin; dextrorphan, 3-methoxymorphinan, 3-hydroxymorphinan; 5-acetylamino-6-amino-3-methyluracil as decomposition product of 5-acetylamino-6-formylamino-3-methyluracil, 1-methylxanthine, respectively) of these substrates were analyzed by capillary electrophoretic techniques. No sample pretreatment other than enzymatic hydrolysis of the conjugated compounds was applied. Assays based on micellar electrokinetic capillary chromatography are shown to allow simultaneous and unambiguous phenotyping with mephenytoin and dextromethorphan or mephenytoin and caffeine. Simultaneous screening for all three polymorphisms with a single injection of a hydrolyzed urine is shown to be possible via use of multiwavelength absorption detection only. Phenotypes determined by electrokinetic capillary techniques are shown to agree with those obtained by analysis with customary assays based on high-performance liquid chromatography.