Evaluation of Clarithromycin Pharmacokinetics after Single and Repeated oral Administration of Atorvastatin in Hyperlipidemic Wistar Rats

Abstract

To evaluate the clarithromycin pharmacokinetics after atorvastatin single and repeated dose administration in induced hyperlipidemic Wistar rats. A standard cholesterol diet (2% cholesterol) was used to induce hyperlipidemia and feed was given to rats for 6-8 weeks. Group’s allocation as follows: G1-G3: Induced hyperlipidemic rats pretreatment of atorvastatin as a single dose followed by clarithromycin single doses of 10, 20 and 100 mg/kg; G4-G6: Induced hyperlipidemic rats pretreatment of atorvastatin for 7 consecutive days followed by clarithromycin single doses of 10, 20 and 100 mg/kg; G7-G8: Atorvastatin treated hyperlipidemia rat livers harvested on day 1 and 7 post dose; G9-G10: Concomitant administration of atorvastatin and clarithromycin in presence and absence of hyperlipidemia for biliary and urinary excretion studies. Effect of atorvastatin on hyperlipidemia and alterations of clarithromycin kinetics due to various states of hyperlipidemia like induced, reduced and absence of hyperlipidemia was evaluated. The Cmax and AUC0–t of clarithromycin on day 1 was found to be 0.56 ± 0.061 µg/mL and 2.4 ± 0.59 µg. h/mL for 10 mg/kg; 1.60 ± 0.24 µg/mL and 9.48 ± 3.05 µg.h/mL for 20 mg/kg; 14.9 ± 3.87 µg/mL and 113 ± 41.4 µg.h/mL for 100 mg/mL, respectively and similarly on day 7 clarithromycin Cmax and AUC0–t was 0.47 ± 0.08 µg/mL and 1.81 ± 0.44 µg.h/mL for 10 mg/kg; 1.34 ± 0.121 µg/mL and 5.61 ± 0.66 µg.h/mL for 20 mg/kg; 12.1 ± 3.3 µg/mL and 67.4 ± 16.9 µg. h/mL for 100 mg/kg, respectively. The in-vitro clarithromycin results suggesting down / up regulation of CYP mediated metabolism in induced and reduced hyperlipidemia rats. The % dose of clarithromycin in biliary excretion was significantly increased (P<0.05) after atorvastatin pretreatment in induced hyperlipidemic rats as compared nonhyperlipidemic rats. The % dose excretion of clarithromycin in urine showed almost similar results across the groups. Clarithromycin pharmacokinetics was considerably affected by hyperlipidemia and also reported that recovered kinetics and metabolism in presence of atorvastatin and compared on day 1 and 7. In-vitro up regulation of clarithromycin metabolism on day 7 was observed in induced hyperlipidemic rat liver homogenates. The decreased area under the curve of clarithromycin in hyperlipidemic rats after co-administration of