An in vitro interethnic comparison of monoamine oxidase activities between Japanese and Caucasian livers using rizatriptan, a serotonin receptor 1B/1D agonist, as a model drug.
OBJECTIVE
Monoamine oxidase (MAO) is located in human liver, and catalyses the oxidative deamination step of many xenobiotics. However, whether there exists an interethnic difference in MAO activities has, to our knowledge, not been clarified. We aimed to assess the MAO type A (MAO-A) involvement in the metabolic pathway of rizatriptan (RIZ), an antimigraine 5-hydroxytryptamine (5-HT)1B/1D agonist, and the interethnic difference in MAO activities between Caucasians and Japanese using RIZ as a model drug in in vitro experiments.


METHODS
Oxidative deaminase activities were determined with the subcellular fractions of Japanese livers and the microsomal fraction of Caucasian livers using RIZ, 5-HT (MAO-A substrate) and 2-phenylethylamine (PEA) (MAO-B substrate) as substrates.


RESULTS
The oxidative deaminase activities of RIZ vs. 5-HT were highly (r = 0.87 and 0.96, P < 0.001) correlated with each other in both the microsomal and mitochondrial fractions of Japanese livers. Subsequent results were obtained from in vitro experiments using liver microsomes based upon these findings. The oxidative deaminase activities of RIZ were inhibited completely by the nanomolar-order concentration of clorgyline and Ro 41-1049 (MAO-A selective inhibitors), but not by that of Ro 16-6491 (MAO-B selective inhibitor). The majority of the mean Michaelis-Menten values for three substrates toward MAO obtained from six Japanese and six Caucasian liver microsomes reached no significant differences between the two ethnic groups. The mean microsomal oxidative deaminase activities assessed in 18 Japanese and 20 Caucasian livers using the three substrates also showed no significant differences between the two ethnic groups.


CONCLUSIONS
RIZ is mainly metabolized by MAO-A and the in vitro oxidative deaminase activities mediated via MAO-A and -B do not appear to differ between Japanese and Caucasians.
Iwasa
T
T
Drug Metabolism, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. iwasatk@banyu.co.jp
Sano
H
H
Sugiura
A
A
Uchiyama
N
N
Hara
K
K
Okochi
H
H
Nakagawa
K
K
Yasumori
T
T
Ishizaki
T
T
D044466:Asian People; D003641:Deamination; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism*; D014230:Triazoles / Q000378:metabolism*; D014363:Tryptamines; D044465:White People
D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C093622:rizatriptan; D008995:Monoamine Oxidase