Garré B, Shebany K, Gryspeerdt A, Baert K, van der Meulen K, Nauwynck H, Deprez P, De Backer P, Croubels S
Department of Pharmacology, Toxicology, Biochemistry, and Organ Physiology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
Antimicrob Agents Chemother. 2007 Dec;51(12):4308-14. doi: 10.1128/AAC.00116-07. Epub 2007 Sep 10.
The purpose of this study was twofold. The first aim was to evaluate the oral bioavailability and pharmacokinetics (PKs) of acyclovir in horses after intravenous (i.v.) administration and after oral administration of acyclovir and its prodrug, valacyclovir. Second, we aimed to combine these PK data with pharmacodynamic (PD) information, i.e., 50% effective concentrations (EC(50) values) from in vitro studies, to design an optimal dosage schedule. Three treatments were administered to healthy adult horses: 10 mg of acyclovir/kg of body weight delivered as an i.v. infusion over 1 h, 20 mg of acyclovir/kg administered as tablets by nasogastric intubation, and 20 mg of valacyclovir/kg administered as tablets by nasogastric intubation. Total plasma concentrations were measured by a high-performance liquid chromatography method combined with fluorescence detection, while unbound plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. The peak concentration of i.v. acyclovir was approximately 10 mug/ml for both the total and the unbound plasma concentrations. The mean half-life of elimination was between 5.05 h (total concentration) and 11.9 h (unbound concentration). Oral administration of acyclovir resulted in low maximum concentration in plasma (C(max)) and poor bioavailability. A 10-times-higher C(max) and an 8-times-higher bioavailability were achieved with oral administration of valacyclovir. The i.v. administration of 10 mg/kg acyclovir and the oral administration of 20 mg/kg valacyclovir achieved concentrations within the sensitivity range of equine herpesvirus type 1 (EHV-1). The higher bioavailability of valacyclovir makes it an attractive candidate for the prophylactic and/or therapeutic treatment of horses infected with EHV-1. The results from the PK/PD modeling showed that a dosage of 40 mg/kg valacyclovir, administered three times daily, would be sufficient to reach plasma concentrations above the EC(50) values.
本研究目的有二。首要目标是评估静脉注射（i.v.）阿昔洛韦以及口服阿昔洛韦及其前体药物伐昔洛韦后，阿昔洛韦在马体内的口服生物利用度和药代动力学（PKs）。其次，我们旨在将这些PK数据与药效学（PD）信息相结合，即体外研究中的50%有效浓度（EC(50)值），以设计出最佳给药方案。对健康成年马进行了三种治疗：以10毫克阿昔洛韦/千克体重静脉输注1小时、经鼻胃管插管给予20毫克阿昔洛韦/千克体重片剂、经鼻胃管插管给予20毫克伐昔洛韦/千克体重片剂。通过高效液相色谱法结合荧光检测测定总血浆浓度，而通过液相色谱 - 串联质谱法测定游离血浆浓度。静脉注射阿昔洛韦的总血浆浓度和游离血浆浓度的峰值浓度约为10微克/毫升。消除的平均半衰期在5.05小时（总浓度）至11.9小时（游离浓度）之间。口服阿昔洛韦导致血浆中最大浓度（C(max)）较低且生物利用度较差。口服伐昔洛韦可使C(max)提高10倍，生物利用度提高8倍。静脉注射10毫克/千克阿昔洛韦和口服20毫克/千克伐昔洛韦所达到的浓度在1型马疱疹病毒（EHV - 1）的敏感范围内。伐昔洛韦较高的生物利用度使其成为预防和/或治疗感染EHV - 1马匹的有吸引力的候选药物。PK/PD建模结果表明，每天给药三次、剂量为40毫克/千克伐昔洛韦足以使血浆浓度达到高于EC(50)值。
