DETERMINATION OF THE MAJOR CIRCULATING METABOLITES OF PERILLYL ALCOHOL

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Perillyl alcohol (NSC 641066), a naturally occurring monoterpene, is now undergoing preclinical evaluation as an antitumor agent at the National Cancer Institute. We have developed a specific assay for perillyl alcohol involving its extraction from plasma into tert-butyl methyl ether followed by capillary gas chromatography with mass spectrometric detection. However, our preliminary studies in mice indicated that perillyl alcohol is extensively and rapidly metabolized; at no time post administration could perillyl alcohol be detected. Investigation of the chemical structure of chromatographic peak components following administration of perillyl alcohol revealed the major circulating metabolites to be perillic acid and dihydroperillic acid. Hence, development of an assay for perillyl alcohol has focussed on the metabolites of perillyl alcohol. The assay has subsequently been utilized to investigate perillyl alcohol (via its metabolites) pharmacokinetics in dogs. The method permits simultaneous quantitation of both metabolites with a linear dynamic range of the assay extending from 0.25 to 10 micro g/ml.