EFFECT OF VALPROIC ACID ON PHARMACOKINETICS OF ACTIVE METABOLITES OF CYCLOPHOSPHAMIDE IN MICE
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概要
- 論文の詳細を見る
The effects of valproic acid (VPA) on pharmacokinetics of cyclophosphamide (CPM) alkylating metabolites were investigated in male BALB/c mice. The pharmacokinetics of CPM alkylating metabolites was found to be dose-dependent representing the decrease of formation and elimination rates of the metabolites. A nonlinear increase of area under blood concentration of CPM alkylating metabolites-time curve (AUC) occurred with increasing CPM dose of 100,200,and 300 mg/kg body weight. The effects of VPA (100 mg/kg dose) coadministered with CPM were similar to those of the increase of the CPM dose in preventing the activation of CPM and the elimination of its alkylating metabolites. The delayed disposition of CPM alkylating metabolites resulted in a 1.5-fold increase (p<0.02) of AUC which was considered the most important pharmacokinetic parameter in the CPM therapy. VPA which was injected i. p. at a dose of 100,200,or 300 mg/kg increased the pentobarbital induced-sleep time by 81,138,or 192%, respectively. In order to assess the effect of VPA on drug metabolizing enzyme (s) activity in humans, the ratio of daily urinary 6-hydroxycortisol to 17-hydroxycorticosteroids, which can reflect cytochrome P-450 activity, was determined in 5 healthy volunteers. The ratio was rapidly and significantly decreased (p<0.05) and this reduction continued during VPA administration. These findings and those reported in the literature concerning CPM metabolism suggest that the delay of CPM alkylating metabolites elimination resulted in part from microsomal enzyme (s) inhibition by VPA.
- 公益社団法人日本薬学会の論文
著者
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GOTO Mitsuyoshi
Department of Hospital Pharmacy Nagoya Memorial Hospital
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JOHNO Ikuo
Department of Internal Medicine Nagoya Memorial Hospital
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KITAZAWA Shikifumi
Department of Internal Medicine Nagoya Memorial Hospital
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Johno I
Department Of Internal Medicine Nagoya Memorial Hospital:department Of Hospital Pharmacy School Of M
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Kitazawa S
Nihon Univ. Chiba Jpn
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YAMASHINA HAJIME
Department of Hospital Pharmacy, Tenri Hospital
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Yamashina H
Nagoya Memorial Hospital Nagoya Jpn
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Yamashina Hajime
Department Of Hospital Pharmacy Tenri Hospital
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KITAZAWA Shikifumi
Department of Hospital Pharmacy, Keio University School of Medicine
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YAMASHINA Hajime
Department of Hospital Pharmacy
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KITAZAWA Shikifumi
Department of Hospital Pharmacy, Keio University Hospital
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