International Journal of Drug Research and Technology

EVALUATION OF PHARMACOKINETIC DRUG INTERACTION BETWEEN PDE 5 INHIBITOR, SILDENAFIL AND HDAC INHIBITORS, SAHA AND MS275 IN SCID MICE

Abstract

Saranya N1,2,3, Thippeswamy BS2*, Chandrasekhar KB3 and Mahamad Yunus Mahat

Combining a cytotoxic drug with a non-cytotoxic drug to reduce adverse effects associated with cytotoxic drugs, without compromising efficacy, is one of the widely pursued approach in cancer research. In order to optimize the dose or prevent adverse effects, it is important to understand the potential drug-drug interaction that may occur between such combinations. In the present study we have evaluated pharmacokinetic drug interaction between phosphodiesterase (PDE) inhibitor Sildenafil (SDFL) and histone deacetylase inhibitors (HDACi, SAHA and MS-275) in mice. SDFL (50 mg/kg i.p.) was administered alone or in combination with SAHA (50 mg/kg i.p.) and MS-275 (35 mg/kg p.o.) to separate set of animals. At predetermined time points, blood samples were collected and plasma was separated and analysed for SDFL, SAHA and MS-275 concentrations using HPLC. Co-administration of SAHA significantly (*p<0.05) enhanced the systemic exposures of SDFL in mice. Mean time to reach peak SDFL plasma concentrations (Tmax) increased by 2 fold. The mean SDFL AUC0-24 when administered in combination with SAHA (15,620 ng*h/mL) was approximately 50% greater than the mean AUC0-24 when SDFL was administered alone (10,630 ng*hr/mL). Further, in presence of SAHA, SDFL was eliminated slowly with mean t1/2 value of 1.74 h in comparison to 0.95 h when administered alone. Accordingly, the SDFL oral clearance was found to be increased (~3 fold) significantly (*p<0.05) when co-administered with SAHA than when given alone. Similarly, Mean plasma clearance of SDFL was ~3 fold higher and t1/2 increased by ~2 fold when administered with MS-275 than alone. Further, mean plasma AUC0-24 of SDFL increased by ~70% in presence of MS-275 than when given alone, thereby, clearly demonstrating the pharmacokinetic drug-drug interaction between HDAC inhibitors and PDE inhibitor. In conclusion Coadministration of SDFL with SAHA/MS-275 resulted into pharmacokinetic drug-drug interactions that lead to altered pharmacokinetic of SDFL in SCID mice. Whereas SAHA and MS275 pharmacokinetics remained unchanged when coadministered with SDFL. To the best of our knowledge, this is the first study to document an in vivo drug interaction between these drugs in mice