Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene.

OBJECTIVE: This study aimed to investigate the importance of cytochrome P(450) enzymes for the reported interaction between tramadol and warfarin. MATERIALS AND METHODS: Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19. RESULTS: Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition. CONCLUSION: The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.

High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study.

BACKGROUND: Acyclovir (ACV) has been used for over two decades to treat herpes virus infections. Serious neurological adverse side effects have occurred during ACV treatment in patients with renal failure, but the cause of the symptoms remains unknown. We hypothesized that increased concentrations of the ACV main metabolite 9-carboxymethoxymethylguanine (CMMG) correlated to these symptoms. METHODS: We conducted an observational study from 1991 to mid 1999 based on samples sent for analysis of ACV concentration from various hospital departments in Sweden. Patients with neuropsychiatric symptoms (NS+, n=49) were compared with patients without symptoms (NS-, n=44). ACV and CMMG concentrations were analysed by HPLC. Medical records were analysed for symptoms and compared with pertinent cases identified from Medline. RESULTS: The serum CMMG levels were significantly higher in the NS+ group (mean=34.1 micro mol/l, 95% confidence interval 23.4-46.1) compared with the NS- group (mean=4.7 micro mol/l, 95% confidence interval 3.3-6.6; P<0.001). CMMG was the strongest predictor in a receiver-operating characteristics curve analysis (ROC), based on 77 patients, of ACV-related neuropsychiatric symptoms. The ROC curve for CMMG demonstrated that neuropsychiatric symptoms could be predicted with a sensitivity of 91% and a specificity of 93% with the use of a cut-off value of 10.8 micro mol/l of CMMG. Thirty-five of 49 patients in the NS+ group showed levels exceeding this concentration compared with only three of 44 of patients in the NS- group (P<0.001). ACV exposure, ACV concentration, creatinine clearance and creatinine concentration were weaker but statistically significant predictors. Haemodialysis reduced CMMG and ACV levels and relieved the symptoms. CONCLUSIONS: The determination of CMMG levels in serum may be a useful tool in supporting the diagnosis of ACV-associated neuropsychiatric symptoms. Furthermore, the monitoring of CMMG levels may prevent the emergence of symptoms.

The pharmacokinetics of ketobemidone are not affected by CYP2D6 or CYP2C19 phenotype.

The pharmacokinetics of orally administered ketobemidone were investigated in three groups of healthy volunteers with respect to cytochrome P450 (CYP) 2D6 and CYP2C19 phenotypes: extensive metabolisers (EMs) of debrisoquine and mephenytoin (EMdeb/EMmeph), poor metabolisers (PMs) of debrisoquine (PMdeb/EMmeph) and poor metabolisers of mephenytoin (PMmeph/EMdeb). Peak plasma concentration, oral clearance, area under the plasma concentration-time curve, half-life, volume of distribution and mean residence time were not significantly different among the three groups. There was no correlation between oral clearance of ketobemidone and debrisoquine or mephenytoin metabolic ratios. Further, the urinary excretion of ketobemidone and norketobemidone was not affected by the phenotype for either CYP2D6 or CYP2C19. However, a substantial variation in plasma concentration was observed within all three groups. The results indicate that the metabolism of ketobemidone is not dependent on CYP2D6 or CYP2C19. PMs of debrisoquine or mephenytoin, as well as patients who are concomitantly treated with inhibitors of CYP2D6 or CYP2C19, are not expected to be at higher risk of adverse effects. However, due to the interindividual variability in plasma levels of ketobemidone, independent of phenotype, individual dosing based on the clinical response and therapeutic drug monitoring is recommended.