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Pharmacokinetics, in vitro absorption and metabolism of perillyl alcohol, a chemopreventive and chemotherapeutic agent

O'Brien, Zhihong Zhang
http://rave.ohiolink.edu/etdc/view?acc_num=osu1078118089

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Pharmacy.
Perillyl alcohol (POH) is a metabolite of the essential oil’s major component, d-limonene. It is currently in phase I and II clinical trials as a chemopreventive and chemotherapeutic agent. Previous pharmacokinetic studies using a GC/MS method detected POH metabolites, but not POH itself. In addition, there was inadequate metabolism and absorption information available for POH. This project aimed to develop a more sensitive GC/MS method for the quantification of POH. Additionally, a LC/MS assay method was developed to probe the Phase II metabolism of POH. The absorption and metabolism of POH was investigated in both rats and humans. Finally, bioavailability of POH in humans was estimated based on the in vivo and in vitro correlation of POH hepatic clearance. The quantification limits for POH, PA (perillic acid), cis- and trans-DHPA (dihydroperillic acid), using a GC/MS method, were <10 ng/ml. The assay was validated in rat and human plasma with the within-run and between-run coefficients of variation all less than 8%. The LC/MS assay method was able to detect POH and its metabolites but the method has yet to be fully validated. The oral bioavailability in the rat was 4.5%. Plasma POH levels in patients receiving oral dose of 500 mg/m2 were below 10 ng/ml. The low in vivo exposure of POH was primarily caused by its metabolism in the GI tract and in liver. In vitro Caco-2 permeability studies suggested that the GI tract was highly permeable to POH. An in vitro rat hepatocyte study result indicated an oral bioavailability of 4%, which agreed well with the measured bioavailability of 4.5% in rat. Accordingly, POH bioavailability in the human was estimated to be 2%. POH was rapidly converted to phase I and phase II metabolites after oral dosing. Its major phase II metabolites included conjugates of cysteine, acetylcysteine, glucuronide and glutathione. This study also provided evidence that two isomers of PA were produced as metabolites.
Kenneth Chan (Advisor)
278 p.
perillyl alcohol; absorption; metabolism; in vitro-in vivo correlation; bioavailability; GC/MS; LC/MS

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Citations

  • O'Brien, Z. Z. (2004). Pharmacokinetics, in vitro absorption and metabolism of perillyl alcohol, a chemopreventive and chemotherapeutic agent [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1078118089

    APA Style (7th edition)

  • O'Brien, Zhihong. Pharmacokinetics, in vitro absorption and metabolism of perillyl alcohol, a chemopreventive and chemotherapeutic agent. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1078118089.

    MLA Style (8th edition)

  • O'Brien, Zhihong. "Pharmacokinetics, in vitro absorption and metabolism of perillyl alcohol, a chemopreventive and chemotherapeutic agent." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1078118089

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.