Effect of Silibinin on the Pharmacokinetics of Pyrazinamide and Pyrazinoic Acid in Rats

Abstract

ABSTRACT:Pyrazinamide (PZA) is widely used in combination with other drugs in chemotherapy for tuberculosis. However, the dose-related liver injury is the main adverse effect of PZA and its metabolite [pyrazinoic acid (PA)]. Silibinin is the main flavonoid extracted from milk thistle (Silybum marianum), and it displays hepatoprotective properties. This study investigates the pharmacokinetics of PZA and PA and their interaction with silibinin in rats. The parallel study design was divided into six groups: PZA alone, PZA ؉ long-term silibinin exposure, PZA ؉ concomitant short-term silibinin exposure, PA alone, PA ؉ long-term silibinin exposure, and PA ؉ concomitant short-term silibinin exposure groups. The results indicate that the distribution ratio of PZA from bile to blood [area under the curve (AUC) bile /AUC blood ] in the PZA ؉ long-term silibinin exposure and PZA ؉ concomitant short-term silibinin exposure groups was also not significantly different when compared with the PZA alone group. However, the bile-to-blood distribution ratio of PA was significantly decreased in the PA ؉ long-term silibinin exposure and the PA ؉ concomitant short-term silibinin exposure groups. On PZA administration, the blood, but not bile, levels of PA were markedly increased in the PZA ؉ long-term silibinin exposure and PZA ؉ concomitant short-term silibinin exposure groups, but the bile-to-blood ratio of PA was decreased. These results suggest that the excretion pathway of PA may be blocked by silibinin through xanthine oxidase and hepatobiliary excretion.

The Pharmacokinetics of Silymarin Is Altered in Patients with Hepatitis C Virus and Nonalcoholic Fatty Liver Disease and Correlates with Plasma Caspase-3/7 Activity

“…Therefore, the elevated plasma levels of phase II conjugates of silymarin may result primarily from alterations in hepatic excretion processes rather than from increased phase II metabolism. Similar increases in flavonolignan exposures have been reported in a rat model of cirrhosis where an approximately 2-fold increase in plasma AUC for SA and SB conjugates was correlated with a 50% reduction in the bile/blood exposure ratio for SA and SB conjugates in cirrhotic rats compared with control (Wu et al, 2008). In humans, decreased biliary excretion of flavonolignan conjugates may potentially influence the efficacy of silymarin as a result of reduced enterohepatic recycling and return of parent flavonolignans via portal blood.…”

Comparing the regenerative effects of silymarin and apricot on liver regeneration after partial hepatectomy in rats

“…Silymarin acts in four different ways: as an antioxidant, absorber, stabilizer and regulator [15]. The results of many experimental studies conducted on hepatoprotective effects of silymarin were briefly reported by Suchy et al and Wu and Tsai [15,16]. Our previous study focused on regenerative effects of 5% SDOA consumption after PH in rats [4].…”

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a1H NMR based metabolomics approach

“…tions of uric acid related metabolites demonstrated severe metabolism disturbance induced by PZA. In addition, XOD was also involved in the rapid oxidation of PZA to its metabolites, pyrazinoic acid or 5-hydroxy-pyrazinamide in the liver, 24,25 with stronger toxicity producing severe hepato-toxicity. In addition, pyrazinoic acid could inhibit the renal tubular secretion of uric acid, aggravating hyperuricaemia.…”