米诺环素在鲤、氧阿苯达唑在鲫体内的代谢研究暨鲤CYP450的初步研究
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摘要
中国是一个渔业大国。由于鱼病的泛滥,各种各样的药物已经被广泛用于鱼病的治疗,渔药的滥用导致了药物在鱼类可食部分的残留。由于我国的气候有明显的季节差异,所以研究药物在不同水温条件下在鱼体内的药动学和残留消除规律可以为该药物给药方案以及休药期的制定提供了理论依据。
本文研究了在冬、夏季水温(10℃和25℃)条件下,米诺环素(MINO)在鲤、氧阿苯达唑(ABZSO)在鲫体内的药动学及残留消除规律。生物样品通过萃取、吹干、浓缩等步骤的前处理,用高效液相色谱法(HPLC)测定样品中药物的含量。本文所建立的标准工作曲线线性关系良好,相关系数(r)均在0.9997以上。试验药品在血浆中的回收率均在88%以上,在组织中的回收率均在73%以上。日间变异系数均小于10%,日内变异系数均小于5%。
对鲤以10mg/kg·bw剂量的MINO口灌溶液、对鲫以10mg/kg·bw剂量的盐酸氧阿苯达唑口灌溶液单次给药进行药物动力学研究表明水温对两种药物的代谢有显著的影响,夏季水温条件下吸收速率相对较快、消除半衰期相对较短。通过药物动力学软件分析表明MINO、ABZSO及其代谢产物的药-时曲线均符合有吸收一室模型。冬季水温(10℃)条件下,MINO的药物动力学参数为：吸收半衰期(t1/2ka)2.65h,达峰时间(Tmax)7.21h,峰浓度(Cmax)2.34μg/mL,消除半衰期(t1/2ke)11.16h,表观分布容积(Vd/F)4.09L/kg,清除率(CLb)0.25L/(h-kg),药时曲线下面积(AUC)59.07μg-h/mL; ABZSO的药动学参数为：t1/2ka3.89h, Tmax10.58h, Cmax3.20μg/mL, t1/2kel6.34h, Vd/F1.99L/kg, CLb0.08L/(h·kg), AUC118.21μg·h/mL; ABZSO2的药动学参数为：t1/2ka6.39h, Tmax12.82h, Cmax0.78μg/mL, t1/2kel2.86h, Vd/F6.43L/kg, CLb0.34L/(h·kg), AUC28.86μg·h/mL。夏季水温(25℃)条件下,MINO的药动学参数为：t1/2ka1.65h, Tmax3.50h, Cmax2.97μg/mL, ti/2ke3.78h, Vd/F2.66L/kg, CLb0.49L/(h-kg), AUC30.77μg·h/mL; ABZSO的药动学参数为：t1/2ka1.29h, Tmax3.80h, Cmax4.39μg/mL, t1/2ke6.72h, Vd/F1.53L/kg, CLb0.19L/(h·kg), AUC63.21μg·-h/mL;ABZSO2的药动学参数为：t1/2ka3.73h, Tmax7.04h, Cmax1.03μg/mL, t1/2ke6.56h, Vd/F4.61L/kg, CLb0.49L/(h·kg), AUC20.52μg·h/mL。
在残留研究中,对鲤以10mg/kg·bw剂量的MINO口灌溶液、对鲫以10mg/kg·bw剂量的盐酸氧阿苯达唑口灌溶液连续给药3d。结果表明水温对MINO在鲤、ABZSO及其代谢产物在鲫体内的消除速率有显著的影响,皮肤中的药物代谢速率与其他组织相比相对较慢。所以,建议两种药物的残留靶组织均为皮肤。若MINO和ABZSO均以10mg/kg·bw的剂量口灌给药,建议MINO的休药期为：在冬季水温(10℃)条件下19d,在夏季水温(25℃)条件下8d；建议ABZSO的休药期为：在冬季水温(10℃)条件下17d,在夏季水温(25℃)条件下10d。
细胞色素P450(CYP450)是由大量同工酶组成的一组超基因家族,对大多数内源性化合物和外源性化合物的代谢起着重要的作用,该酶系在药理学中具有极其重要的研究意义。尽管CYP450对动物体内药物的代谢起着重要的作用,但目前对于该酶的研究主要集中在实验动物和人体上,关于食品动物CYP450酶的研究相对较少。我国是鱼类食品的消费大国,渔药的合理使用与人类的健康及环境安全密切相关。本试验以我国市场需求量大的鲤为研究对象,研究了不同的水温(10℃和25℃)对鲤肝微粒体生化指标的影响；常用磺胺类药物(SD、SMD、SM2)对鲤肝微粒体CYP450生化指标的影响；以氯唑沙宗(CZX)作为探针药物研究不同水温(5℃、10℃、15℃、20℃、25℃、30℃)对鲤CYP2E1同工酶活性的影响。本实验旨在为水产动物CYP450酶系的进一步研究以及指导水产动物合理用药和鱼类用药的安全性问题提供理论基础。具体研究结果如下：
1.水温对鲤肝微粒体CYP450生化指标的影响
通过比较可以看出在冬季水温(10℃)条件下鲤肝细胞色素P450酶的部分生化指标与在夏季水温条(25℃)件下的相比明显偏低,这为解释鱼类在夏季水温(25℃)条件下药物代谢速率会明显高于在冬季水温(10℃)条件下的代谢速率提供了理论依据。该结果为进一步研究细胞色素CYP450亚酶的活性与温度的关系奠定了基础。
2.磺胺类药物对鲤肝微粒体CYP450生化指标的影响
结果表明常用磺胺类药物(SD、SM2、SMM)对鲤肝微粒体蛋白含量,CYPb5的活性、ERND的活性没有明显的影响,对CYP450含量、AND、AH的活性具有明显的抑制作用(P<0.01),这对磺胺类药物在水产动物上的合理应用具有指导意义。
3.温度对CYP2E1同工酶活性的影响
实验结果表明CYP2E1同工酶的Km值(以CZX作为探针)在反应温度为25℃时相对较低,其Vmax(以CZX作为探针)在该温度时相对较高；反应温度对CYP450酶活性的影响能够间接反映水温对鱼类体内药物代谢的影响。由此可见,鱼类在不同水温条件下药物动力学参数的差异主要是由于其CYP450酶在不同温度下的活性差异所造成的。
China is a big fishing country. Due to the prevalence of fish disease, various drugs have been used extensively to control it. The abuse of fishery drugs leads to disposition of residues in the edible parts of treated fish. However, Chinese climate shows significant seasonal variations. So the studies of pharmacokinetics and residues of drugs in fish at different seasons could provide theoretical basis for the formulation of dosage regimen and withdrawal time.
Pharmacokinetics and residues elimination of minocycline(MINO) in carp (Cyprinus carpio) and albendazole sulfoxide(ABZSO) in crucian carp (Carassius auratus) were studied kept at winter water temperature(10℃) and summer water temperature (25℃). The drug concentrations in biological samples were analyzed by means of high-performance liquid chromatography (HPLC) after sample pretreatment steps. The correlation of calibration curves (correlation coeffcients were above0.9997) was all good. The average of experimental drug extraction recoveries were more than88%from plasma and more than73%from other tissues. The coefficients of variation (inter-day and intra-day) were less than10%and5%, respectively.
Fish were administration orally (a single dose of10mg/kg·bw) in the pharmacokinetics group (MINO in carp and ABZSO in crucian carp). The results revealed that the influence of water temperature on the drug metabolism was significant. There were higher absorption rate and shorter elimination half-lives (t1/2ke) compared with those at winter water temperature. The plasma concentration-time data (MINO in carp, ABZSO and ABZSO2in crucian carp) conformed to one-compartment open model at two water temperatures. At winter water temperature(10℃), the pharmacokinetics parameters of MINO:the absorption half-lives(t1/2ka) was2.65h, the peak time(Tmax) was7.21h, the peak concentration (Cmax) was2.34μg/mL, the elimination half-lives(t1/2ke) was11.16h, the distribution volumes(Vd/F) was4.09L/kg, the total body clearances(CLb) was0.25L/(h-kg), the areas under the concentration-time curve(AUC) was59.07μg·h/mL; the pharmacokinetics parameters of ABZSO:t1/2ka was3.89h, Tmax was10.58h, Cmax was3.20μg/mL, t1/2ke was16.34h, Vd/F was1.99L/kg, CLb was0.08L/(h·kg), AUC118.21μg·h/mL; the pharmacokinetics parameters of ABZSO2:t1/2ka was6.39h, Tmax was12.82h, Cmax was0.78μg/mL, t1/2kewas12.86h, Vd/F was6.43L/kg,CLb was0.34L/(h-kg), AUC28.86μg·h/mL. At summer water temperature(25℃), the pharmacokinetics parameters of MINO:t1/2ka was1.65h, Tmax was3.50h, Cmax was2.97μg/mL, t1/2ke was3.78h, Vd/F was2.66L/kg,CLb was0.49L/(h·kg), AUC30.77μg·h/mL; the pharmacokinetics parameters of ABZSO:t1/2ka was1.29h, Tmax was3.80h, Cmax was4.39μg/mL, t1/2ke was6.72h, Vd/F was1.53L/kg, CLb was0.19L/(h·kg), AUC63.21μg·h/mL; the pharmacokinetics parameters of ABZSO2:t1/2ka was3.73h, Tmax was7.04h, Cmax was1.03μg/mL, t1/2ke was6.56h, Vd/F was4.61L/kg, CLb was0.49L/(h·kg), AUC20.52μg·h/mL.
In the residues study, fish were given a multi-dose of10mg/kg·bw (MINO in carp and ABZSO in crucian carp) for3consecutive days by oral gavages. The results showed that the influence of water temperature on the elimination rate (MINO in carp, ABZSO and its metabolites in crucian carp) was significant and the drug metabolic rate in skin was relatively slower than that in other tissues. So the elimination of MINO and ABZSO in skin could be behaved as a reservoir. If fish were administered MINO and ABZSO orally with a single dose(10mg/kg·bw) for several days, the withdrawal periods of MINO could be not less than19d at winter water temperature(10℃) and8d at summer water temperature(25℃), which of ABZSO could be not less than17d and10d, respectively.
Cytochrome P450(CYP450) enzymes represent a superfamily of monooxygenases that play a pivotal role in metabolism of endogenous and exogenous compounds, which have great research significance in pharmacology. The research on CYP450only focused on the experimental animal and human, although it plays an important in animal drug metabolism. The research of CYP450in edible animal was relatively fewer. As China is a big consuming country in fish food, rational use of fishery drug relates closely to human health and experimental safety. The experiment(with carp as object) studied on the influence of water temperature and3sulfonamides(SD, SM2, SMM) on the CYP450biochemical indicators; studied on the influence of reaction temperature(5℃,10℃,15℃,20℃,25℃,30℃) on the CYP2E1-like isoform activity with Chorzoxazone (CZX) as substrate. This experiment provided theoretical basis for further research of fish CYP450and the rational use of fish drug. Detail results are as follows.
1. The influence of water temperature on CYP450biochemical indicators
Some biochemical indicators at winter water temperature(10℃) were lower compared to those at summer water temperature(25℃), which provided theoretical basis for it that fish metabolic rate at summer water temperature(25℃) is higher than that at winter water temperature(10℃). These results laid the foundation for the future research in relationship between temperature and CYP450isoform.
2The influence of3sulfonamides on CYP450biochemical indicators
These results showed that sulfonamides (SD, SM2, SMM) could make the content of liver microsomal protein decreased and make the activity (AND and AH) inhibited significantly (P<0.01); these sulfonamides have no effect on the content of CYPb5or the activity of ERND. Those provided directive significance on the rational use of sulfonamides in fish.
3The influence of temperature on CYP2El-like isoform activity
These results revealed that the Michaelis constant (Km) value of CYP2El-like isoform(with CZX as probe) was minimal and Maximum reaction velocity (Vmax) was maximal at25℃compared with those at other temperatures. The influence of reaction temperature on CYP450activity could reflect the influence of water temperature on drug metabolism in fish indirectly. So variations of fish pharmacokinetic parameters at different water temperatures could be due to the variation of CYP450activity at different temperatures.
本文研究了在冬、夏季水温(10℃和25℃)条件下,米诺环素(MINO)在鲤、氧阿苯达唑(ABZSO)在鲫体内的药动学及残留消除规律。生物样品通过萃取、吹干、浓缩等步骤的前处理,用高效液相色谱法(HPLC)测定样品中药物的含量。本文所建立的标准工作曲线线性关系良好,相关系数(r)均在0.9997以上。试验药品在血浆中的回收率均在88%以上,在组织中的回收率均在73%以上。日间变异系数均小于10%,日内变异系数均小于5%。
对鲤以10mg/kg·bw剂量的MINO口灌溶液、对鲫以10mg/kg·bw剂量的盐酸氧阿苯达唑口灌溶液单次给药进行药物动力学研究表明水温对两种药物的代谢有显著的影响,夏季水温条件下吸收速率相对较快、消除半衰期相对较短。通过药物动力学软件分析表明MINO、ABZSO及其代谢产物的药-时曲线均符合有吸收一室模型。冬季水温(10℃)条件下,MINO的药物动力学参数为：吸收半衰期(t1/2ka)2.65h,达峰时间(Tmax)7.21h,峰浓度(Cmax)2.34μg/mL,消除半衰期(t1/2ke)11.16h,表观分布容积(Vd/F)4.09L/kg,清除率(CLb)0.25L/(h-kg),药时曲线下面积(AUC)59.07μg-h/mL; ABZSO的药动学参数为：t1/2ka3.89h, Tmax10.58h, Cmax3.20μg/mL, t1/2kel6.34h, Vd/F1.99L/kg, CLb0.08L/(h·kg), AUC118.21μg·h/mL; ABZSO2的药动学参数为：t1/2ka6.39h, Tmax12.82h, Cmax0.78μg/mL, t1/2kel2.86h, Vd/F6.43L/kg, CLb0.34L/(h·kg), AUC28.86μg·h/mL。夏季水温(25℃)条件下,MINO的药动学参数为：t1/2ka1.65h, Tmax3.50h, Cmax2.97μg/mL, ti/2ke3.78h, Vd/F2.66L/kg, CLb0.49L/(h-kg), AUC30.77μg·h/mL; ABZSO的药动学参数为：t1/2ka1.29h, Tmax3.80h, Cmax4.39μg/mL, t1/2ke6.72h, Vd/F1.53L/kg, CLb0.19L/(h·kg), AUC63.21μg·-h/mL;ABZSO2的药动学参数为：t1/2ka3.73h, Tmax7.04h, Cmax1.03μg/mL, t1/2ke6.56h, Vd/F4.61L/kg, CLb0.49L/(h·kg), AUC20.52μg·h/mL。
在残留研究中,对鲤以10mg/kg·bw剂量的MINO口灌溶液、对鲫以10mg/kg·bw剂量的盐酸氧阿苯达唑口灌溶液连续给药3d。结果表明水温对MINO在鲤、ABZSO及其代谢产物在鲫体内的消除速率有显著的影响,皮肤中的药物代谢速率与其他组织相比相对较慢。所以,建议两种药物的残留靶组织均为皮肤。若MINO和ABZSO均以10mg/kg·bw的剂量口灌给药,建议MINO的休药期为：在冬季水温(10℃)条件下19d,在夏季水温(25℃)条件下8d；建议ABZSO的休药期为：在冬季水温(10℃)条件下17d,在夏季水温(25℃)条件下10d。
细胞色素P450(CYP450)是由大量同工酶组成的一组超基因家族,对大多数内源性化合物和外源性化合物的代谢起着重要的作用,该酶系在药理学中具有极其重要的研究意义。尽管CYP450对动物体内药物的代谢起着重要的作用,但目前对于该酶的研究主要集中在实验动物和人体上,关于食品动物CYP450酶的研究相对较少。我国是鱼类食品的消费大国,渔药的合理使用与人类的健康及环境安全密切相关。本试验以我国市场需求量大的鲤为研究对象,研究了不同的水温(10℃和25℃)对鲤肝微粒体生化指标的影响；常用磺胺类药物(SD、SMD、SM2)对鲤肝微粒体CYP450生化指标的影响；以氯唑沙宗(CZX)作为探针药物研究不同水温(5℃、10℃、15℃、20℃、25℃、30℃)对鲤CYP2E1同工酶活性的影响。本实验旨在为水产动物CYP450酶系的进一步研究以及指导水产动物合理用药和鱼类用药的安全性问题提供理论基础。具体研究结果如下：
1.水温对鲤肝微粒体CYP450生化指标的影响
通过比较可以看出在冬季水温(10℃)条件下鲤肝细胞色素P450酶的部分生化指标与在夏季水温条(25℃)件下的相比明显偏低,这为解释鱼类在夏季水温(25℃)条件下药物代谢速率会明显高于在冬季水温(10℃)条件下的代谢速率提供了理论依据。该结果为进一步研究细胞色素CYP450亚酶的活性与温度的关系奠定了基础。
2.磺胺类药物对鲤肝微粒体CYP450生化指标的影响
结果表明常用磺胺类药物(SD、SM2、SMM)对鲤肝微粒体蛋白含量,CYPb5的活性、ERND的活性没有明显的影响,对CYP450含量、AND、AH的活性具有明显的抑制作用(P<0.01),这对磺胺类药物在水产动物上的合理应用具有指导意义。
3.温度对CYP2E1同工酶活性的影响
实验结果表明CYP2E1同工酶的Km值(以CZX作为探针)在反应温度为25℃时相对较低,其Vmax(以CZX作为探针)在该温度时相对较高；反应温度对CYP450酶活性的影响能够间接反映水温对鱼类体内药物代谢的影响。由此可见,鱼类在不同水温条件下药物动力学参数的差异主要是由于其CYP450酶在不同温度下的活性差异所造成的。
China is a big fishing country. Due to the prevalence of fish disease, various drugs have been used extensively to control it. The abuse of fishery drugs leads to disposition of residues in the edible parts of treated fish. However, Chinese climate shows significant seasonal variations. So the studies of pharmacokinetics and residues of drugs in fish at different seasons could provide theoretical basis for the formulation of dosage regimen and withdrawal time.
Pharmacokinetics and residues elimination of minocycline(MINO) in carp (Cyprinus carpio) and albendazole sulfoxide(ABZSO) in crucian carp (Carassius auratus) were studied kept at winter water temperature(10℃) and summer water temperature (25℃). The drug concentrations in biological samples were analyzed by means of high-performance liquid chromatography (HPLC) after sample pretreatment steps. The correlation of calibration curves (correlation coeffcients were above0.9997) was all good. The average of experimental drug extraction recoveries were more than88%from plasma and more than73%from other tissues. The coefficients of variation (inter-day and intra-day) were less than10%and5%, respectively.
Fish were administration orally (a single dose of10mg/kg·bw) in the pharmacokinetics group (MINO in carp and ABZSO in crucian carp). The results revealed that the influence of water temperature on the drug metabolism was significant. There were higher absorption rate and shorter elimination half-lives (t1/2ke) compared with those at winter water temperature. The plasma concentration-time data (MINO in carp, ABZSO and ABZSO2in crucian carp) conformed to one-compartment open model at two water temperatures. At winter water temperature(10℃), the pharmacokinetics parameters of MINO:the absorption half-lives(t1/2ka) was2.65h, the peak time(Tmax) was7.21h, the peak concentration (Cmax) was2.34μg/mL, the elimination half-lives(t1/2ke) was11.16h, the distribution volumes(Vd/F) was4.09L/kg, the total body clearances(CLb) was0.25L/(h-kg), the areas under the concentration-time curve(AUC) was59.07μg·h/mL; the pharmacokinetics parameters of ABZSO:t1/2ka was3.89h, Tmax was10.58h, Cmax was3.20μg/mL, t1/2ke was16.34h, Vd/F was1.99L/kg, CLb was0.08L/(h·kg), AUC118.21μg·h/mL; the pharmacokinetics parameters of ABZSO2:t1/2ka was6.39h, Tmax was12.82h, Cmax was0.78μg/mL, t1/2kewas12.86h, Vd/F was6.43L/kg,CLb was0.34L/(h-kg), AUC28.86μg·h/mL. At summer water temperature(25℃), the pharmacokinetics parameters of MINO:t1/2ka was1.65h, Tmax was3.50h, Cmax was2.97μg/mL, t1/2ke was3.78h, Vd/F was2.66L/kg,CLb was0.49L/(h·kg), AUC30.77μg·h/mL; the pharmacokinetics parameters of ABZSO:t1/2ka was1.29h, Tmax was3.80h, Cmax was4.39μg/mL, t1/2ke was6.72h, Vd/F was1.53L/kg, CLb was0.19L/(h·kg), AUC63.21μg·h/mL; the pharmacokinetics parameters of ABZSO2:t1/2ka was3.73h, Tmax was7.04h, Cmax was1.03μg/mL, t1/2ke was6.56h, Vd/F was4.61L/kg, CLb was0.49L/(h·kg), AUC20.52μg·h/mL.
In the residues study, fish were given a multi-dose of10mg/kg·bw (MINO in carp and ABZSO in crucian carp) for3consecutive days by oral gavages. The results showed that the influence of water temperature on the elimination rate (MINO in carp, ABZSO and its metabolites in crucian carp) was significant and the drug metabolic rate in skin was relatively slower than that in other tissues. So the elimination of MINO and ABZSO in skin could be behaved as a reservoir. If fish were administered MINO and ABZSO orally with a single dose(10mg/kg·bw) for several days, the withdrawal periods of MINO could be not less than19d at winter water temperature(10℃) and8d at summer water temperature(25℃), which of ABZSO could be not less than17d and10d, respectively.
Cytochrome P450(CYP450) enzymes represent a superfamily of monooxygenases that play a pivotal role in metabolism of endogenous and exogenous compounds, which have great research significance in pharmacology. The research on CYP450only focused on the experimental animal and human, although it plays an important in animal drug metabolism. The research of CYP450in edible animal was relatively fewer. As China is a big consuming country in fish food, rational use of fishery drug relates closely to human health and experimental safety. The experiment(with carp as object) studied on the influence of water temperature and3sulfonamides(SD, SM2, SMM) on the CYP450biochemical indicators; studied on the influence of reaction temperature(5℃,10℃,15℃,20℃,25℃,30℃) on the CYP2E1-like isoform activity with Chorzoxazone (CZX) as substrate. This experiment provided theoretical basis for further research of fish CYP450and the rational use of fish drug. Detail results are as follows.
1. The influence of water temperature on CYP450biochemical indicators
Some biochemical indicators at winter water temperature(10℃) were lower compared to those at summer water temperature(25℃), which provided theoretical basis for it that fish metabolic rate at summer water temperature(25℃) is higher than that at winter water temperature(10℃). These results laid the foundation for the future research in relationship between temperature and CYP450isoform.
2The influence of3sulfonamides on CYP450biochemical indicators
These results showed that sulfonamides (SD, SM2, SMM) could make the content of liver microsomal protein decreased and make the activity (AND and AH) inhibited significantly (P<0.01); these sulfonamides have no effect on the content of CYPb5or the activity of ERND. Those provided directive significance on the rational use of sulfonamides in fish.
3The influence of temperature on CYP2El-like isoform activity
These results revealed that the Michaelis constant (Km) value of CYP2El-like isoform(with CZX as probe) was minimal and Maximum reaction velocity (Vmax) was maximal at25℃compared with those at other temperatures. The influence of reaction temperature on CYP450activity could reflect the influence of water temperature on drug metabolism in fish indirectly. So variations of fish pharmacokinetic parameters at different water temperatures could be due to the variation of CYP450activity at different temperatures.
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