Andrographis paniculataExtract and Andrographolide Modulate the Hepatic Drug Metabolism System and Plasma Tolbutamide Concentrations in Rats

Abstract

Andrographolide is the most abundant terpenoid of A. paniculata which is used in the treatment of diabetes. In this study, we investigated the effects of A. paniculata extract (APE) and andrographolide on the expression of drug-metabolizing enzymes in rat liver and determined whether modulation of these enzymes changed the pharmacokinetics of tolbutamide. Rats were intragastrically dosed with 2 g/kg/day APE or 50 mg/kg/day andrographolide for 5 days before a dose of 20 mg/kg tolbutamide was given. APE and andrographolide reduced the AUC0–12 h of tolbutamide by 37% and 18%, respectively, compared with that in controls. The protein and mRNA levels and enzyme activities of CYP2C6/11, CYP1A1/2, and CYP3A1/2 were increased by APE and andrographolide. To evaluate whether APE or andrographolide affected the hypoglycemic action of tolbutamide, high-fat diet-induced obese mice were used and treated in the same manner as the rats. APE and andrographolide increased CYP2C6/11 expression and decreased plasma tolbutamide levels. In a glucose tolerance test, however, the hypoglycemic effect of tolbutamide was not changed by APE or andrographolide. These results suggest that APE and andrographolide accelerate the metabolism rate of tolbutamide through increased expression and activity of drug-metabolizing enzymes. APE and andrographolide, however, do not impair the hypoglycemic effect of tolbutamide.

Effect of Andrographolide Co-Administration on Pharmacokinetics of Meloxicam in Rats

“…While elimination half-life and mean residence time of theophylline were shortened about 14 and 17 % in the andrographolide (77 mg/kg) pretreated group rats (Chao et al, 2010). Similarly Andrographis paniculata extract and andrographolide reduced the AUC 0-12h of tolbutamide by 37% and 18%, respectively (Chen et al, 2013). However, no significant effect of andrographolide on pharmacokinetics of warfarin (Hovhannisyan et al, 2006) and midazolam (Wongnawa et al, 2012) was observed.…”

Pharmacokinetics and metabolic elimination of tolbutamide in female rats: Comparison with male rats

“…First, sets of data points were fitted to the following equation I to estimate the apparent Michaelis–Menten kinetic parameters: V = V max × S /( K m + S ), where V , V max , S , and K m are velocity of reaction, maximum reaction velocity, TB concentration, and Michaelis constant, respectively. On the other hand, it was reported that CYP2C6 and CYP2C11 are likely involved in TB 4‐hydroxylase activity in male rats (Chen et al, ; Dostalek et al, ; Wang et al, ). Therefore, assuming the involvement of these two enzymes in the metabolic reaction, the measurements were fitted to the following equation II: V = V max1 × S /( K m1 + S ) + V max2 × S /( K m2 + S ), where K m1 and K m2 correspond to the K m values of the low affinity and high affinity component, respectively.…”

“…where V, V max , S, and K m are velocity of reaction, maximum reaction velocity, TB concentration, and Michaelis constant, respectively. On the other hand, it was reported that CYP2C6 and CYP2C11 are likely involved in TB 4-hydroxylase activity in male rats (Chen et al, 2013;Dostalek et al, 2007;Wang et al, 2010). Therefore, assuming the involvement of these two enzymes in the metabolic reaction, the measurements were fitted to the following equation II:…”

“…Tolbutamide (TB) is one of the representative probe drugs for CYP2C (Becker et al, ; Fukuno et al, ; Velenosi, Fu, Luo, Wang, & Urquhart, ), and previous kinetic studies have implied that TB is metabolized to 4‐hydroxytolbutamide (4‐OH‐TB) by CYP2C6/11 in rats (Chen et al, ; Dostalek et al, ; Wang, Lee, Or, & Yeung, ). The aim of this study was to investigate the pharmacokinetic behavior of TB in female rats and compare with that in male rats.…”

Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats

“…Tolbutamide (TB) is a sulfonylurea derivative used as a hypoglycaemic agent in the management of type 2 diabetes mellitus. Previous kinetic studies suggested that tolbutamide is exclusively metabolized to 4‐hydroxytolbutamide (4‐OH‐TB) in rats as well as in humans and serves as a representative probe drug for CYP2C6/11 (Bogaards et al, ; Chen et al, ; Dostalek et al, ; Pekthong et al, ; Wang, Lee, Or, & Yeung, ). The aims of the present study were to examine whether the change in the expression level of hepatic CYP2C6/11 reflected the metabolic capacity of tolbutamide by conducting enzyme kinetic analysis of tolbutamide 4‐hydroxylation in hepatic microsomes of rats exposed to doxorubicin, and to investigate whether the in vitro enzyme activity is associated with the in vivo pharmacokinetics of total and unbound tolbutamide, while considering changes in the serum albumin concentration.…”