| Research Abstract |
Objectives: Idiosyncratic or type B adverse drug reactions (type B ADR) are characterised by their unpredictability and lack of simple dose-dependency. They occur in a small proportion of patients, and usually the predisposing factors are unknown. We investigated the predisposing factors of type B ADR, seeking for a novel method for the diagnosis and prevention.
Methods: 1. We reviewed drug metabolizing enzymes and the genetic polymorphisms concerning 215 etiologic drugs in 795 cases with drug-induced pneumonia that had been colleded by a nation wide survey in Japan. 2. We assessed 1) the risk factors for type B ADR of anticonvulsants in 371 cases of epileptics, 2)the effects of psychotropic drugs on QT interval in 335 psychiatric inpatients and age- and sex-matched 335 controls, by using logistic regression analysis and/or nonlinear mixed-effect modeling. 3. We analyzed 5-FU/alpha-fluoro-beta-alanine in urine samples of 30 patients under tegafur therapy.
Results: 1. We developed a buccal smear sampling method (swab method) for ge notyping drug metabolizing enzyme genes in cases with type B ADR. 2. Carbamazepine (CBZ) dose and clearance, psychomotor retardation, tube feeding were identified as the risk factors for hyponatremia, leukopenia, and/or liver dysfunction. Pharmacokinetics of CBZ depended significantly on cytochrome P4503A5 genotypes but the relevance to the ADR under CBZ therapy is unknown. 3. Flunitrazepam was found to be a drug with the highest relative risk (RR=1.6, p<0.05) of the QT prolongation. 4. Urine 5-FU/alpha-fluoro-beta-alanine ration may be a potential marker of the susceptibility to tegafur toxicity.
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