Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine–alprazolam interaction in patients with psychosomatic disease
Objectives. Administration of fluvoxamine (FLV) with concomitant benzodiazepines is common in clinical situations. We studied the effects of the coadministration of FLV on plasma concentrations of alprazolam (ALP). We also studied the effects ofCYP2C19*2 orCYP2C19*3 on these drug interactions. Methods. The subjects were 23 Japanese outpatients all concomitantly treated with FLV either before or after monotherapy with ALP. We measured the plasma concentrations of ALP and FLV using a column-switching, high-performance liquid chromatographic method with ultraviolet detection. TheCYP2C19*2 orCYP2C19*3 alleles were identified using a polymerase chain reaction analysis. Results. Coadministration with FLV produced significant, on average 58%, increases in the plasma concentrations of ALP (P<0.001). There were, however, wide variations in the interactive effects of the coadministration of FLV on the plasma concentrations of ALP. While there were some subjects who had greater increases in plasma ALP concentrations, more than 100%, in response to the coadministration of FLV among the subjects with no mutated or one mutated allele, there are no subjects who had increases in plasma ALP concentrations of more than 50% among the subjects with two mutated alleles. The differences of these variances among the three genotype groups reached a level of significance (P<0.05). Conclusion. Coadministration of FLV significantly increased the plasma concentrations of ALP compared with ALP monotherapy. Wide variations were observed in the drug interactions, with the CYP2C19 genotype possibly being related to these interactions.