Mikov M, Boni N S, Al-Salami H, Kuhajda K, Kevresan S, Golocorbin-Kon S, Fawcett J P
School of Pharmacy, University of Otago, Dunedin, New Zealand.
Eur J Drug Metab Pharmacokinet. 2007 Jan-Mar;32(1):7-12. doi: 10.1007/BF03190984.
Previous studies in our laboratory have shown that the semisynthetic bile acid derivative, sodium 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate (MKC), has hypoglycemic activity. The aim of this study was to investigate the relationship between the pharmacokinetics and hypoglycemic activity of MKC in healthy and diabetic rats. Groups of healthy and alloxan-induced diabetic rats were dosed intravenously (i.v.) and orally with MKC (4 mg/kg). Blood samples were taken before administration of the dose and at 20, 40, 60, 80, 120, 150, 180, 210 and 240 minutes post-dose. MKC serum concentration was measured by HPLC, and pharmacokinetic parameters determined using the WinNonlin program. The absolute bioavailability of MKC was found to be low in healthy and diabetic rats (29 and 23% respectively) and was not significantly different between the two groups. Mean residence time (MRT), volume of distribution (Vd) and half-life (t1/2) of MKC after oral administration were significantly lower in diabetic than in healthy rats (21, 31 and 29% respectively). After the i.v. dose, the change in blood glucose concentration was not significant in either healthy or diabetic rats. After the oral dose, the decrease in blood glucose concentration was significant, reaching a maximum decrease from baseline of 24% in healthy rats and 15% in diabetic rats. The results suggest that a first-pass effect is crucial for the hypoglycemic activity of MKC, indicating that a metabolite of MKC and/or interference with metabolism and glucose transport is responsible.
我们实验室之前的研究表明，半合成胆汁酸衍生物3α,7α-二羟基-12-氧代-5β-胆烷酸钠（MKC）具有降血糖活性。本研究的目的是探讨MKC在健康大鼠和糖尿病大鼠体内的药代动力学与降血糖活性之间的关系。将健康大鼠和四氧嘧啶诱导的糖尿病大鼠分组，静脉注射（i.v.）和口服MKC（4mg/kg）。在给药前以及给药后20、40、60、80、120、150、180、210和240分钟采集血样。通过高效液相色谱法（HPLC）测定MKC血清浓度，并使用WinNonlin程序确定药代动力学参数。发现MKC在健康大鼠和糖尿病大鼠中的绝对生物利用度较低（分别为29%和23%），两组之间无显著差异。糖尿病大鼠口服MKC后的平均驻留时间（MRT）、分布容积（Vd）和半衰期（t1/2）显著低于健康大鼠（分别为21%、31%和29%）。静脉注射给药后，健康大鼠和糖尿病大鼠的血糖浓度变化均不显著。口服给药后，血糖浓度显著降低，健康大鼠血糖浓度从基线最大降低24%，糖尿病大鼠降低15%。结果表明，首过效应对于MKC的降血糖活性至关重要，这表明MKC的一种代谢产物和/或对代谢及葡萄糖转运的干扰起了作用。
