Wong H, Kumar S, Rurak D W, Kwan E, Abbott F S, Riggs K W
Faculty of Pharmaceutical Sciences, Department of Obstetrics and Gynecology, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
Drug Metab Dispos. 2000 Aug;28(8):912-9.
The ontogeny of valproic acid (VPA) disposition and metabolism was investigated in developing lambs and adult sheep (Dorset or Suffolk breed). Specifically, we wished to investigate the role of glucuronidation and beta-oxidation on VPA elimination during development. Catheters were implanted in a carotid artery, a jugular vein, and the urinary bladder in 10-day-old (10 d; n = 8), 1-month-old (1 M; n = 4), and 2-month-old lambs (2 M; n = 5). In adult sheep (n = 5), catheters were implanted in a femoral artery and vein. After the administration of a 10 mg/kg VPA i.v. bolus, serial blood samples and cumulative urine samples were collected for 36 h in the adult ewes and for 72 h in the lambs. Due to saturable protein binding, age-related differences in VPA clearance were more obvious when examining the total body clearance of unbound drug (Cl(u)tb). Mean Cl(u)tb increased significantly with age up to 2 months (10 d = 2.65 +/- 1.16 ml/min/kg; 1 M = 5.11 +/- 2.49 ml/min/kg; 2 M = 12.84 +/- 3.88 ml/min/kg) before decreasing to adult levels (7.73 +/- 2.64 ml/min/kg). Similarly, the urinary recovery of the major metabolite, VPA-glucuronide, was significantly less in 10 d lambs (29.2 +/- 16.0% of the dose) when compared with the adult and 2 M groups (both approximately 74% of the dose). No differences with age were observed in the portion of the dose excreted as the beta-oxidation metabolite, 2-n-propyl-3-oxopentanoic acid. The results suggest that alterations in Cl(u)tb with age may be attributable to postnatal development of enzymes involved in VPA glucuronidation.
在发育中的羔羊和成年绵羊（多塞特或萨福克品种）中研究了丙戊酸（VPA）处置和代谢的个体发生情况。具体而言，我们希望研究葡萄糖醛酸化和β-氧化在发育过程中对VPA消除的作用。将导管植入10日龄（10 d；n = 8）、1月龄（1 M；n = 4）和2月龄羔羊（2 M；n = 5）的颈动脉、颈静脉和膀胱中。在成年绵羊（n = 5）中，将导管植入股动脉和静脉。静脉注射10 mg/kg VPA推注后，在成年母羊中收集36小时的系列血样和累积尿样，在羔羊中收集72小时的样本。由于蛋白质结合具有饱和性，在检查未结合药物的总体清除率（Cl(u)tb）时，VPA清除率的年龄相关差异更为明显。平均Cl(u)tb在2个月龄之前随年龄显著增加（10 d = 2.65 +/- 1.16 ml/min/kg；1 M = 5.11 +/- 2.49 ml/min/kg；2 M = 12.84 +/- 3.88 ml/min/kg），然后降至成年水平（7.73 +/- 2.64 ml/min/kg）。同样，主要代谢物VPA-葡萄糖醛酸苷的尿回收率在10日龄羔羊中（占剂量的29.2 +/- 16.0%）显著低于成年组和2月龄组（均约占剂量的74%）。作为β-氧化代谢物2-正丙基-3-氧代戊酸排泄的剂量部分未观察到年龄差异。结果表明，Cl(u)tb随年龄的变化可能归因于参与VPA葡萄糖醛酸化的酶的出生后发育。
