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Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent

Li, Fang
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592

Abstract Details

2007, PhD, University of Cincinnati, Pharmacy : Pharmaceutical Sciences.
Numerous drug agents exhibit low and erratic oral bioavailability. Drug metabolizing enzymes (DMEs) such as cytochrome P450 3A4 (CYP3A4) and efflux transporters (DTs) such as P-gp, BCRP and MRP2 are major barriers that restrict oral drug bioavailability. Inhibition of CYP3A4 by ritonavir is a clinically proven strategy for enhancing oral bioavailability. Based on the observation that grapefruit juice (GFJ) consumption inhibits CYP3A4 activity and enhances the systemic exposure of CYP3A4 substrates, extensive efforts have been made to isolate the CYP3A4 inhibitory components of GFJ. Accordingly, BAS 100, a spiro-ortho-ester, isolated by Bioavailability Systems Inc, is a promising CYP3A4 inhibitor. In preliminary studies BAS 100 was observed to considerably enhance the pharmacokinetics of saquinavir, an antiretroviral drug metabolized by CYP3A4. This study was undertaken to gain mechanistic insights into BAS 100 as a bioavailability enhancer. First, employing human liver microsomal incubations we observed that BAS 100 was a potent competitive inhibitor of CYP3A4 with an IC50 to be 37.0 nM. Comparatively, ritonavir, a well-known CYP3A4 inhibitor, had an IC50 of 43.0 nM. In addition, BAS 100 demonstrated mechanism-based CYP3A4 inhibition, with the KI and Kinact for BAS 100 and ritonavir being 0.37 μM and 0.73 min-1 and 0.36 μM and 0.25 min-1, respectively. We then evaluated the induction potential of BAS 100 on hepatic CYP3A4 expression and activity after long-term exposure. Although, BAS 100 and ritonavir increased CYP3A4 transcription, they markedly inhibited the CYP3A4 activity. Using MDCK cell lines stably transfected with MDR1, which encodes P-gp, bcrp1 or MRP2 genes we further compared BAS 100 and ritonavir for their ability to inhibit drug transport. Finally, we conducted a pilot “proof-of-concept” in vivo study to investigate the effects of BAS 100 on the bioavailability of docetaxel, an anti-cancer agent metabolized by CYP3A4 and exhibiting extremely poor oral bioavailability. In FVB mice BAS 100 and ritonavir markedly increased the exposure of docetaxel by 29- and 28-fold, respectively. Taken together, our study indicates that BAS 100 is very similar to ritonavir in its effect on inhibiting CYP3A4 activity and has the potential to enhance the systemic exposure to drugs with low oral bioavailability
Dr. Pankaj Desai (Advisor)
178 p.
Health Sciences, Pharmacology
CYP3A; Inhibition; Induction; Bioavailability; Drug transporters

Recommended Citations

Citations

  • Li, F. (2007). Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592

    APA Style (7th edition)

  • Li, Fang. Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592.

    MLA Style (8th edition)

  • Li, Fang. "Investigation of BAS 100, a Naturally Occurring CYP3A Inhibitor, as a Bioavailability Boosting Agent." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195794592

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.