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THE EFFECT OF CYP2D6 AND CYP2C19 GENOTYPES ON THE METABOLISM
OF AMITRIPTYLINE IN JAPANESE PSYCHIATRIC PATIENTS.
*Dept, Psychiatry, Shiga Univ. of Med.
Science, **Takashima General Hospital.
***Nagahama Seijukai Hospital, ****Dept,
Psychiatry, Niigata Univ. Sch. of Med.,
*****Saitama Kounan Hospital, Japan.
Hirokane G*,**,
Morita S*, Yokono A*，***,
Someya T****, Takahashi S*****,
Okawa M*, Shimoda K*
We investigated the effect of the CYP2C19 and CYP2D6
genotypes on the metabolism of amitriptyline(AT) in Japanese
psychiatric patients. Steady-state concentrations of AT and
its metabolites (nortriptyline(NT), trans-10-hydroxynortriptyline(EHNT),
cis-10-hydroxynortriptyline(ZHAT), trans-10-hydroxyamitriptyline(EHAT)
and cis-10-hydroxyamitriptyline(ZHAT)) in fifty Japanese patients(male:female=20
:30) who were orally administered AT hydrochloride were determined
by high-performance liquid chromatography. For genotyping of
CYP2C19 and CYP2D6, polymerase chain reaction
methods were used. The allele frequencies of the CYP2C19*2,
CYP2C19*3, CYP2D6*5 and CYP2D6*10 were
28.0%, 5.0%, 5.0% and 47.0%, respectively. Significantly higher
plasma concentrations of AT corrected for dose and body weight
in the subjects with two mutated alleles of CYP2C19 than
those with no mutated alleles of CYP2C19 were observed
(no mutated alleles vs. two mutated allele: 35.5 ±18.0 vs 64.0
± 25.2 ng/ml/mg/kg, p=0.024). Significantly higher AT/NT ratio,
which is representative of the desmethylation ratio of AT, was
also observed in the subjects with two mutated alleles of CYP2C19
than those with no mutated alleles(no mutated alleles vs. two
mutated alleles= 1.27 ± 0.58 vs 3.40 ± 1.03, p=0.001). Trend
for higher NT/EHNT ratio, which is representative of the hydroxylation
ratio of NT, in the subjects with two mutated alleles of CYP2D6
than those with no mutated alleles of CYP2D6 was observed
(no mutated alleles vs. two mutated alleles= 0.73±0.40 vs 1.31±0.81,
p=0.069). Trend for higher plasma concentrations of total hydroxylated
metabolites of AT(=EHAT+ZHAT), in the subjects with two mutated
alleles of CYP2C19 than those with no mutated alleles
of CYP2C19 was observed (no mutated alleles vs. two mutated
alleles= 9.47 ± 5.65 vs 17.80 ± 8.95, p=0.050). Therefore,
the genotyping of CYP2C19 is useful to predict the plasma
concentrations of AT and the capacity to desmethylate AT. The
oxidation of AT to EHAT and ZHAT is accelerated in subjects
with homozygotes of mutated alleles of CYP2C19 in order
to compensate the decreased capacity to desmethylate AT(This
research has been approved by the Ethics Committee of Shiga
University of Medical Science). |
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日本人精神疾患患者におけるamitriptylineの代謝とcytochrome
P450(CYP)2C19およびCYP2D6の遺伝子型との関連
*滋賀医大・医・精神、**公立高島総合病院・精神、***長浜青樹会病院、****新潟大･医･精神、*****埼玉
江南病院
広兼元太*，**、森田幸代*、横野 文*，***、染矢俊幸****、高橋三郎*****、大川匡子*、下田和孝*
目的：三環系抗うつ薬amitriptyline(AT)の代謝には大きな個体差が存在し、その代謝にはCYP2C19やCYP2D6の関与が示唆されている。そこで日本人におけるATの代謝（脱メチル化と水酸化）とCYP2C19およびCYP2D6の遺伝子型との関連について検討した。
方法：対象はATを2週間以上服用中で本研究の趣旨を説明し、同意が得られた50名（男性20名，女性30名）で、ATの投与量
は25〜225mg/dayであった。ATとその脱メチル化物nortriptyline(NT)、水酸化代謝物trans-及びcis-10-hydroxyamitriptyline(それぞれEHAT、ZHAT),
trans-および cis-10-hydroxynortriptyline (それぞれEHNT、ZHNT)の血漿中濃度をHPLCにより定量
した。また末梢血からDNAを抽出し、CYP2C19*1、CYP2C19*2、CYP2C19*3はPCR-RFLP法により、CYP2D6*1、CYP2D6*2、CYP2D6*5、CYP2D6*10はPCR法により検出した。尚、本研究は滋賀医科大学医学部倫理委員会の承認を受けている。
結果及び結論：CYP2C19*2、CYP2C19*3、CYP2D6*5、CYP2D6*10のallele
frequencyはそれぞれ28.0%、5.0%、5.0%、47.0%であった。CYP2C19変異遺伝子ホモ接合体を持つ個体では正常遺伝子ホモ接合体を持つ個体に比して、体重あたり投与量
で補正したATの血漿中濃度が有意に高く（35.5 ± 18.0 vs 64.0
± 25.2 ng/ml/mg/kg, p=0.024）、また脱メチル化率AT/NTもCYP2C19の変異遺伝子ホモ接合体を持つ個体では正常遺伝子のホモ接合体を持つ個体に比して有意に高かった（1.27
± 0.58 vs 3.40 ± 1.03, p=0.001）。CYP2D6変異遺伝子ホモ接合体を持つ個体では正常遺伝子ホモ接合体を持つ個体に比較してNTの水酸化率NT/EHNTが高い傾向が認められた(0.73
± 0.40 vs 1.31 ± 0.81, p=0.069)。さらにCYP2C19変異遺伝子ホモ接合体をもつ個体では、正常遺伝子ホモ接合体を持つ個体に比して体重あたり投与量
で補正したAT水酸化体（EHAT+ZHAT）の血漿中濃度が高い傾向が認められた（9.47
± 5.65 vs 17.80 ± 8.95, p=0.050）。以上より、ATの血漿濃度や脱メチル化能の予測にはCYP2C19のgenotypingが有用であること、CYP2C19変異遺伝子ホモ接合体をもつ脱メチル化能の低い個体では代償的にATの水酸化がすすむことが推察された。 |
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