Oral Pharmacokinetics of Sildenafil in the presence of CYP3A4-inducer and -inhibitor using cannulated and non-cannulated male Swiss Albino mice

Satish Kumar; Rajkumar Jadi; Bhagheeradha Lakkimsetti; Surendra Yadav Ravulapalli; Sudhir Kumar Tiwari; Pratima Srivastava; Ritu Paliwal; Lakshman E. Rajagopalan

Volume : IX, Issue : III, March - 2019

Oral Pharmacokinetics of Sildenafil in the presence of CYP3A4-inducer and -inhibitor using cannulated and non-cannulated male Swiss Albino mice

Satish Kumar, Rajkumar Jadi, Bhagheeradha Lakkimsetti, Surendra Yadav Ravulapalli, Sudhir Kumar Tiwari, Pratima Srivastava, Ritu Paliwal, Lakshman E. Rajagopalan

Abstract :

Objective: Sildenafil is majorly metabolized by Cytochrome P450 (CYP450) isoform 3A4. The latter is responsible for the metabolism of more than 50% of the drugs. It is involved in multiple clinically relevant drug–drug interactions. To evaluate the mice pharmacokinetics model as a drug– drug interaction model by using Sildenafil in the presence of Carbamazepine (CYP3A4 inducer) and Ketoconazole (CYP3A4 inhibitor) in male Swiss albino mice. Also, efforts have been put–forth to employ cannulated mice and compare the data with the non–cannulated mice. Methodology: Ketoconazole and Carbamazepine (10 mg/kg, PO) were dosed for 6 days in different groups of mice. On day 6 Sildenafil (10 mg/kg, PO) was dosed 15 minutes post Ketoconazole and Carbamazepine administration. Two control groups were dosed with Sildenafil alone. Blood samples were collected through retro–orbital plexus for sparse sampling and jugular vein for cannulated mice at 0.25, 0.5, 1, 2, 4 and 8 h post Sildenafil administration and analyzed by LC–MS/MS. Results: Ketoconazole increased the Cmax and AUClast of Sildenafil by 146% and 219% in non–cannulated and 63% and 194% in cannulated mice respectively, as compared to control group. Carbamazepine decreased the Cmax and AUClast of Sildenafil by 36% in non–cannulated mice and 61% and 58% in cannulated mice respectively, as compared to control group. There was no significant difference in the pharmacokinetic parameters of Sildenafil in cannulated and non–cannulated groups. The study reflects to the underlying drug–drug interactions which can attribute in the pharmacokinetics of Sildenafil, in the presence of drugs, which are inducers and inhibitors of CYP3A4. Also, that cannulated mice can be employed to reduce the animal usage by one third without compromising the data quality.