Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles.
OBJECTIVE
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 of CYP2C19(*)2 or CYP2C19(*)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. The CYP2C19(*)2 or CYP2C19(*)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).


CONCLUSIONS
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.
Suzuki
Yutaro
Y
Department of Psychiatry, Niigata University Graduate School of Medical and Dental Science, 1-757 Asahimachi, 951-8510, Niigata, Japan.
Shioiri
Toshiki
T
Muratake
Tatsuyuki
T
Kawashima
Yoshiaki
Y
Sato
Satoshi
S
Hagiwara
Mieko
M
Inoue
Yoshimasa
Y
Shimoda
Kazutaka
K
Someya
Toshiyuki
T
D000328:Adult; D000483:Alleles; D000525:Alprazolam / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D014151:Anti-Anxiety Agents / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D005260:Female; D016666:Fluvoxamine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000525:Alprazolam; D014151:Anti-Anxiety Agents; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D016666:Fluvoxamine; D006899:Mixed Function Oxygenases; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human