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In man a great interindividual variability exists in the oxidative capacity to metabolize drugs. A major factor contributing to this phenomenon is the genetically determined hydroxylation-capacity of the cytochrome P450 enzyme system. The cytochrome P450 system comprises of several isozymes. For several isozymes (CYP2D6, CYP2C) a genetically based hydroxylation capacity has been demonstrated. A frequency distribution of the clearance shows a bimodal distribution with poor and extensive metabolizers. Applying standard dosing schemes of the drugs that are predominantly metabolised by these isozymes, a considerable number of patients will be intoxicated because of poor metabolism. In general, cytochrome P450 capacity is limited and substrate-affinity is high. Henceforth cytochrome P450 isozymes are likely targets for pharmacokinetic interactions.

In man a great interindividual variability exists in the oxidative capacity to metabolize drugs. A major factor contributing to this phenomenon is the genetically determined hydroxylation-capacity of the cytochrome P450 enzyme system. The cytochrome P450 system comprises of several isozymes. For several isozymes (CYP2D6, CYP2C) a genetically based hydroxylation capacity has been demonstrated. A frequency distribution of the clearance shows a bimodal distribution with poor and extensive metabolizers. Applying standard dosing schemes of the drugs that are predominantly metabolised by these isozymes, a considerable number of patients will be intoxicated because of poor metabolism. In general, cytochrome P450 capacity is limited and substrate-affinity is high. Henceforth cytochrome P450 isozymes are likely targets for pharmacokinetic interactions.

In man a great interindividual variability exists in the oxidative capacity to metabolize drugs. A major factor contributing to this phenomenon is the genetically determined hydroxylation-capacity of the cytochrome P450 enzyme system. The cytochrome P450 system comprises of several isozymes. For several isozymes (CYP2D6, CYP2C) a genetically based hydroxylation capacity has been demonstrated. A frequency distribution of the clearance shows a bimodal distribution with poor and extensive metabolizers. Applying standard dosing schemes of the drugs that are predominantly metabolised by these isozymes, a considerable number of patients will be intoxicated because of poor metabolism. In general, cytochrome P450 capacity is limited and substrate-affinity is high. Henceforth cytochrome P450 isozymes are likely targets for pharmacokinetic interactions.

In the course of 1979 the Netherlands Centre for Monitoring of Adverse Reactions to Drugs (NARD) received a remarkably large number of reports on patients with unusual and complex psychic disturbances, attributed to the use of the then recently marketed hypnotic triazolam. The interpretation of the data was difficult, however, and several questions could at that time not be properly answered. In the past 10 years a specific benzodiazepine withdrawal syndrome has been identified, showing many similarities with the disturbances as reported in association with triazolam. In addition similar adverse experiences with triazolam have been reported in many other countries. Tablets containing 1 mg and 0.5 mg triazolam, as were widely used in The Netherlands, have in the mean time been globally removed from the market. It is concluded that the 'triazolam syndrome' may be explained as a combination of strong benzodiazepine effects and withdrawal phenomena. The ultra short half-life of triazolam and the high doses used may have contributed to the problems as observed in The Netherlands. The signal perceived by the NARD appears to have been a valuable warning, rightly casting doubt on the safety of triazolam and the original dosage recommendations.