BUP exhibits low oral bioavailability (Foral<15%) due to extensive presystemic oxidative (CYP) and conjugative (UGT) metabolism . Previous studies in our lab identified chrysin, ginger extract, α-mangostin, pterostilbene and silybin as potential inhibitors of BUP metabolism. Their inhibitory potencies and biorelevant GI solubilites were also determined. Additionally, the intestinal (Fg) and hepatic (Fh) availabilities and ultimately Foral of BUP were predicted by extrapolating in vitro kinetic data using the well-stirred model. In this study, the effect of these inhibitor treatments on three output variables i.e. predicted Foral, exposure (AUC∞PO) and total clearance (CLtot) of BUP were extrapolated using the well-stirred model. A simulated population dataset (n=10,000) was generated using Monte Carlo simulations to evaluate the effect of inhibitor treatments on the variability in the output variables under two scenarios: #1: High variability - 60% CV in intestinal intrinsic clearance [CLint (GW)] and 41% CV in hepatic intrinsic clearance [CLint (hep)] and #2 Low variability - 40% CV in CLint (GW) and 25% CV in CLint (hep). A sensitivity analysis was also performed to identify the kinetic parameters showing strong influence on the three output variables and denoted using the Spearman-rank correlation coefficient (r). BUP was predicted to show Foral, AUC∞PO and CLtot of 3.4±2.2%, 344±327 ng*min/ml and 1050±126 ml/min, respectively. The intestinal CYP CLint was predicted to be the most sensitive input variable affecting Foral (r = -0.85) and AUC∞PO (r = -0.75) whereas hepatic CYP CLint showed a strong positive relationship with CLtot (r=0.97) of BUP. Of the 5 inhibitors, only pterostilbene and silybin improved the predicted Foral of BUP from 3.4±2.2% to 75±5.6% and 36±9.4% respectively, which is ≥ to the reported sublingual bioavailability (Fsublingual) of BUP (35%). However, despite showing drastic enhancement in the Foral, the variability in the predicted AUC∞PO of BUP was not significantly affected. Hence, a simulated dose-dependent study was performed to identify a suitable dose of pterostilbene that can achieve a predicted Foral≥Fsublingual of BUP and also exhibit drastic reduction in the variability associated with the predicted output variables, especially AUC∞PO. A ten fold lower dose (from 21 mg to 2.1 mg) of pterostilbene improved the mean predicted Foral to 35±8.0% and showed impressive reduction in the variability in AUC∞PO from 95% to 49% (case#1) or from 50% to 28% (case#2). These results provide strong support to our strategy of co-administering GRAS or dietary compounds such as pterostilbene with BUP to inhibit its oxidative and conjugative metabolism. This will ultimately help in achieving sufficiently high and less variable Foral and AUC∞PO of BUP following oral administration to produce its intended therapeutic effects. The use of this inhibitor strategy might also be extended to other drugs similar to BUP that exhibit poor Foral due to extensive first pass metabolism.
Funding: Center for Innovative Technology, Matching Funds Grant#MF14S-007-LS.
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