The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats.
The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats.
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DOI：
10.1111/fcp.12157
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发表时间：
2016-02
影响因子：
2.9
通讯作者：
Hilmer SN
中科院分区：
文献类型：
--
作者：
Mach J;Huizer-Pajkos A;Mitchell SJ;McKenzie C;Phillips L;Kane A;Jones B;de Cabo R;Cogger V;Le Couteur DG;Hilmer SN
异烟肼是结核病的一线治疗药物;然而，其使用受到肝毒性的限制。异烟肼的药代动力学和肝毒性的药物相关差异尚不确定。我们的目标是在年轻人中调查这些（3 ± 0个月，n = 26）和老年人（23.0 ± 0.2个月，n = 27）雄性Fischer 344大鼠接受低或高剂量异烟肼或溶剂毒性方案后（2天内4次给药/天;低剂量：100、75、75、75 mg/kg;高剂量：150、105、105、105 mg/kg i. p.，每3 h一次）。末次给药后15小时，对动物实施安乐死，并制备血清和肝脏用于分析。异烟肼给药增加了幼龄动物的血清肝毒性标志物（丙氨酸和天冬氨酸转氨酶），但未增加老龄动物的血清肝毒性标志物（丙氨酸和天冬氨酸转氨酶），仅在幼龄动物中高剂量时达到显著性。异烟肼给药在两种剂量下均导致幼龄动物坏死增加的趋势。相比之下，在接受异烟肼治疗的老年动物中，微泡脂肪变性增加，仅在低剂量下达到显著性（老年动物中脂肪变性患病率：溶媒1/9，异烟肼4/5; P < 0.05）。异烟肼处理组中，毒性中间体乙酰肼和肼的浓度老年组高于青年组（P < 0.05）。两种剂量下，幼龄动物肝细胞色素P450 2 E1活性均高于老龄动物（P < 0.05）。对参与异烟肼代谢的任何其他测量酶（N-乙酰转移酶、酰胺酶、谷胱甘肽-S-转移酶）均未观察到其他年龄效应。这些结果表明，年龄相关的异烟肼药代动力学变化可能导致不同的毒性模式，并证实标准的肝毒性标志物不能检测到异烟肼诱导的微泡脂肪变性。
Isoniazid is the first-line treatment for tuberculosis; however, its use is limited by hepatotoxicity. Age-related differences in isoniazid pharmacokinetics and hepatotoxicity are uncertain. We aimed to investigate these in young (3 ± 0 months, n = 26) and old (23.0 ± 0.2 months, n = 27) male Fischer 344 rats following a low- or high-dose toxic regimen of isoniazid or vehicle (4 doses/day over 2 days; low: 100, 75, 75, 75 mg/kg; high: 150, 105, 105, 105 mg/kg i.p. every 3 h). Fifteen hours after the last dose, animals were euthanized and sera and livers were prepared for analysis. Isoniazid treatment increased serum hepatotoxicity markers (alanine and aspartate transaminase) in young animals but not in old animals, and only reached significance with the high dose in young animals. Isoniazid treatment caused a trend towards an increase in necrosis in young animals with both doses. In contrast, microvesicular steatosis was increased in old isoniazid-treated animals, reaching significance only with the low dose (steatosis prevalence in old: vehicle 1/9, isoniazid 4/5; P < 0.05). Among isoniazid-treated animals, concentrations of toxic intermediates acetylhydrazine and hydrazine were higher in old than young animals (P < 0.05). With both doses, hepatic cytochrome P450 2E1 activity was higher in young animals compared with old (P < 0.05). There were no other age effects seen on any of the other measured enzymes involved in isoniazid metabolism (N-acetyl transferase, amidase, glutathione-S-transferase). These results show age-related changes in isoniazid pharmacokinetics may contribute towards differential patterns of toxicity and confirm that standard hepatotoxicity markers do not detect isoniazid-induced microvesicular steatosis.
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影响因子：
4.1
作者：
Metushi IG;Nakagawa T;Uetrecht J
通讯作者：
Uetrecht J
影响因子：
4.3
作者：
Jimenez-Lopez, Jose M;Cederbaum, Arthur I
通讯作者：
Cederbaum, Arthur I
影响因子：
9.6
作者：
Fountain, FF;Tolley, E;Self, TH
通讯作者：
Self, TH
影响因子：
5.3
作者：
COECKE, S;VANDENBERGHE, Y;ROGIERS, V
通讯作者：
ROGIERS, V
影响因子：
3.8
作者：
Ko, Hyeok-Jin;Lee, Eun Woo;Choi, In-Geol
通讯作者：
Choi, In-Geol