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首页> 外文期刊>Biochemical Pharmacology >Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice
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Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice

机译：野生型和BPHL敲除小鼠对肠稳定性，渗透性和吸收肠道稳定性，渗透性和吸收的影响

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摘要

Biphenyl hydrolase-like protein (BPHL) is a novel human serine hydrolase that was originally cloned from a breast carcinoma cDNA library and shown to convert valacyclovir to acyclovir and valganciclovir to ganciclovir. However, the exclusivity of this process has not been determined and, indeed, it is possible that a number of esterases/proteases may mediate the hydrolysis of valacyclovir and similar prodrugs. The objectives of the present study were to evaluate thein situintestinal permeability and stability of valacyclovir in wildtype (WT) andBphlknockout (KO) mice, as well as thein vivooral absorption and intravenous disposition of valacyclovir and acyclovir in the two mouse genotypes. We found thatBphlknockout mice had no obvious phenotype and thatBphlablation did not alter the jejunal permeability of valacyclovir duringin situperfusions (i.e., 0.54?×?10?4in WT vs. 0.53?×?10?4?cm/s in KO). Whereas no meaningful changes occurred between genotypes in the gene expression of proton-coupled oligopeptide transporters (i.e., PepT1, PepT2, PhT1, PhT2), enzymatic upregulation of Cyp3a11, Cyp3a16, Abhd14a and Abhd14b was observed in some tissues ofBphlknockout mice. Most importantly, we found that valacyclovir was rapidly and efficiently hydrolyzed to acyclovir in the absence of BPHL, and that hydrolysis was more extensive after the oral vs. intravenous route of administration (for both genotypes). Taken as a whole, BPHL is not obligatory for the conversion of valacyclovir to acyclovir either presystemically or systemically.
机译：双苯基水解酶样蛋白（BPH1）是一种新型人丝氨酸水解酶，其最初克服乳腺癌cDNA文库，并显示将Valacyclovir转化为Acyclovir和Valganciclovir至Ganciclovir。然而，该方法的排他性尚未确定，并且实际上，许多酯酶/蛋白酶可能介导伐昔洛维韦和类似的前药的水解。本研究的目的是评估野生型（WT）andbphlkockout（KO）小鼠的缬氨酸素渗透性和稳定性，以及在两种小鼠基因型中的Vivooral吸收和Valacyclovir和Acyclovir的静脉内处置。我们发现，在定期灌注期间（即0.54，0.54，0.54×10？4英寸Wt与0.53？×10？4？×10？×10？4？cm / s，没有明显的表型没有明显的表型并未改变伐昔洛韦的Jejunal渗透性（即0.54×10？4英寸wt与0.53？×10？4？cm / s）。然而，在质子偶联的寡肽转运蛋白的基因表达中发生了有意义的变化（即，Pept1，Pept2，pht1，pHT2），在某些组织中观察到CYP3A11，CYP3A16，ABHD14A和ABHD14B的酶促上调。最重要的是，在没有BPHL的情况下，伐昔洛维尔在没有BPH的情况下迅速且有效地水解给Acyclovir，并且在口腔与静脉施用途径后，水解更加广泛（对于两种基因型）。作为一个整体，BPHL不义务转化Valacyclovir至Acyclovir在系统上或系统性上。

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