Administration route-dependent pharmacokinetic and biopharmaceutical features of steppogenin

Purpose: This study aimed to develop liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for steppogenin and to assess its bioavailability (BA) and biopharmaceutical features in mice when administered via different route. Methods: The LC-MS/MS method for steppogenin was validated and used to investigate the pharmacokinetics of steppogenin in mice. A calibration curve was prepared in the range of 1–1,000 ng/mL of calibration standards and three levels of quality control samples (3, 125, and 750 ng/mL). Thereafter, the pharmacokinetics and BA of steppogenin were investigated following its administration via four different routes (i.e., intravenous [IV], subcutaneous [SC], intraperitoneal [IP], and per oral [PO]). Results: The linearity, inter- and intra-day precision, accuracy, and stability results were within 15% of the coefficient of variance (CV, %). Mean recoveries and the matrix effect of steppogenin were 68.06–89.47% and 59.03–66.72% with less than 11.87% and 9.031% of CV, respectively. BA of steppogenin administered via IV, SC, IP, and PO was determined as 100%, 84.7–96.0%, 54.0–54.6%, and 5.73–10.0%, respectively. P-glycoprotein (P-gp) efflux and first-pass phase II metabolism could have led to the low PO and moderate IP BA of steppogenin. The co-administration of a P-gp inhibitor (i.e., verapamil or D-α-tocopherol polyethylene glycol 1000 succinate) significantly increased the oral BA of steppogenin by 315% and 149%, respectively. Conclusion: The favorable pharmacokinetic features of steppogenin administered as IV or SC injection could result in its better therapeutic efficacy than when administered IP or PO. To improve oral BA, formulation strategies could incorporate inhibitors of P-gp-mediated efflux and first-pass metabolism.