In vitro inhibition and induction of human cytochrome P450 enzymes by SIPI5357, a potential antidepressant

Biopharmaceutics & Drug Disposition
Gaoning FanJin Yang

Abstract

This study investigated the in vitro drug-drug interaction potential of SIPI5357, an arylalkanol-piperazine derivative used in the treatment of depression. Drug-drug interaction occurs via inhibition or induction of enzymes involved in their metabolism. In human liver microsomes, SIPI5357 showed the strongest inhibition of CYP2D6, followed by CYP3A4 (testosterone) and CYP2C8. Inhibition was observed in a concentration-dependent manner, with IC50 values of 18.45 µM, 36.63 µM (CYP3A4/testosterone), 89.23 µM, respectively. SIPI5357 was predicted not to cause significant metabolic drug-drug interaction via inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP3A4 (midazolam) because the IC50 values for these enzymes were both >100 µM (200 times maximum plasma concentration [Cmax ]). SIPI5357 showed a mixed model inhibition of CYP2D6 (Ki = 11.12 µM). The value of [I]/Ki for CYP2D6 inhibition by SIPI5357 is below the FDA cut-off value of 0.1; it is therefore reasonable to assume that SIPI5357 will not cause significant CYP2D6 inhibition. However, positive controls (50 µM omeprazole and 25 µM rifampin) caused the anticipated CYP induction, but the highest concentration of SIPI5357 (5 µM; 10 times plasma Cmax ) had a minimal effect on CY...Continue Reading

References

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Citations

Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen

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