Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype.

BACKGROUND: Codeine is widely used as an analgesic and antitussive drug. The analgesic effect of codeine is mediated by its metabolite morphine, which is formed by the polymorphically expressed enzyme CYP2D6; therefore poor metabolizers have no analgesia after administration of codeine. Like other opiates, codeine causes a delay of gastric emptying and spastic constipation. It is not yet known whether the effect on gastrointestinal motility is mediated by codeine or its metabolite morphine. METHODS: To test the hypothesis that the metabolite morphine is responsible for the effects of codeine on gastrointestinal motility, a randomized, double-blind, two-way crossover study was performed. The orocecal transit time was studied in five extensive and five poor metabolizers of sparteine with the sulfasalazine-sulfapyridine method, assuming that no effects are observed in poor metabolizers because negligible amounts of morphine are formed. RESULTS: No differences of orocecal transit times were observed between extensive metabolizers and poor metabolizers after oral placebo administration. However, after oral codeine administration orocecal transit time was significantly prolonged in extensive metabolizer but not poor metabolizer subjects. All pharmacokinetic parameters of codeine showed no differences between extensive metabolizers and poor metabolizers. The pharmacokinetic parameters (mean +/- SD) of the metabolite morphine were significantly different between extensive metabolizer and poor metabolizer subjects (peak serum concentration, 13.9 +/- 10.5 versus 0.68 +/- 0.15 pmol/ml; area under the serum concentration-time curve, 27.8 +/- 16.0 versus 1.9 +/- 0.7 hr.pmol/ml; total amount of morphine excreted in urine, 0.160 +/- 0.036 versus 0.015 +/- 0.007 mumol). CONCLUSIONS: Because the orocecal transit time prolongation after codeine administration was observed only in extensive metabolizers, the effect of codeine on gastrointestinal motility, like the analgesia, is mediated by its metabolite morphine.

Disposition and bioavailability of the beta 1-adrenoceptor antagonist talinolol in man.

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective beta 1-adrenoceptor antagonist talinolol (Cordanum--Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (Cmax) of 631 +/- 95 ng mL-1 (mean +/- SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC0-infinity) was 1433 +/- 153 ng h mL-1. The following parameters were estimated: terminal elimination half life (t 1/2), 10.6 +/- 3.3 h; mean residence time, 11.6 +/- 3.1 h; volume of distribution, 3.3 +/- 0.5 L kg-1; and total body clearance, 4.9 +/- 0.6 mL min-1 kg-1. Within 36 h 52.8 +/- 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 +/- 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a Cmax of 168 +/- 67 ng mL-1 was reached after 3.2 +/- 0.8 h. The AUC0-infinity was 1321 +/- 382 ng h mL-1. The t 1/2 was 11.9 +/- 2.4 h. 28.1 +/- 6.8% of the dose or 55.0 +/- 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 +/- 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 +/- 15% (95% confidence interval, 36-69%).(ABSTRACT TRUNCATED AT 250 WORDS)

Elucidation of the structure of talinolol metabolites in man. Determination of talinolol and hydroxylated talinolol metabolites in urine and analysis of talinolol in serum.

The objective of this study was to determine the structure of talinolol metabolites formed and the amounts excreted in urine. Talinolol metabolites in urine were identified by comparing their HPLC retention times and their GC-MS profile with those of previously characterized reference compounds. The metabolites were quantified by HPLC with a normal-phase silica column, a single chloroform extraction and UV detection. Less than 1% of an administered dose was found in urine as hydroxylated talinolol. Other metabolites could be excluded. A sensitive method to determine talinolol in serum and a simple method for analysis of talinolol in urine are described. These methods were found to be precise and accurate for the measurement of talinolol in samples obtained from patients during chronic talinolol treatment as well as from healthy volunteers after a single dose of talinolol.

The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 in volunteers with T-tube after cholecystectomy.

The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 were investigated in 6 female volunteers (age: 26-69 years) 9-14 days after cholecystectomy and T-tube construction. After a single oral dose of 50 mg AWD 26-06 as an aqueous solution the amount of the unchanged substance was determined in serum, T-tube bile and urine with a special HPLC-method. The concentration maximum was reached earlier and higher in bile (60 +/- 22 min; 10.8 +/- 5.7 micrograms/ml) than in serum (73 +/- 28 min; 0.98 +/- 0.53 micrograms/ml). During the whole observation time of 24 h the AWD 26-06 concentration in bile was 2-21-fold higher than in serum. In mean 2.3 +/- 1.5% of the administered dose were eliminated unchanged by bile and 12.2 +/- 5.9% by urine. More than 70% of the dose were metabolized. The results gave a hint at active liver transport processes and an enterohepatic recirculation. A drug interaction was observed with valproic acid on the metabolic level. The great interindividual variability of pharmacokinetic data can be caused by the heterogeneity of the subject group and a genetic polymorphism in the metabolism of AWD 26-06. The bile sampling by means of a T-tube is a simple but effective method under consideration of special conditions.