PHARMACOKINETICS OF ACTIVE-DRUG METABOLITES AFTER ORAL-ADMINISTRATIONOF PERILLYL ALCOHOL, AN INVESTIGATIONAL ANTINEOPLASTIC AGENT, TO THE DOG

The monocyclic terpene d-limonene, a major component in many citrus es sential oils (1-3), has been used for many years as a flavoring agent, food additive, and fragrance (1, 2). It was recently demonstrated tha t limonene exhibits both chemopreventive and therapeutic effects again st chemically induced mammary tumors in rats (4-10). Mechanistic studi es revealed that limonene inhibits the posttranslational isoprenylatio n of 21-26 kDa cellular proteins implicated in cell growth and prolife ration (11-13). Limonene is extensively metabolized by a variety of ma mmalian species (14-17). Its principal circulating metabolites identif ied in the rat, perillic acid and dihydroperillic acid, are also effec tive inhibitors of isoprenylation and cellular proliferation in vitro (17, 18). Furthermore, one of the metabolic precursors of these compou nds, perillyl alcohol (16), is considerably more potent than limonene against the in vivo rat mammary tumor models (19). A preliminary repor t of an ongoing phase 1 clinical trial with limonene indicated that a single oral dose of 100 mg/kg is well tolerated (20). However, an extr apolation based upon the rat mammary tumor regression studies suggests that the minimum human dose requirement would be 1000 mg/kg/day (6). The administration of such a large dose, which amounts to more than 80 ml of an oily volatile liquid, on a continuing basis may cause proble ms. Thus, perillyl alcohol is currently being developed as a clinical candidate at the National Cancer Institute because of its greater pote ncy than limonene, which may enable potentially effective systemic con centrations of the active principals to be achieved at considerably lo wer doses.(1) The pharmacokinetic behavior of perillyl alcohol in prec linical animal models has not been reported previously. This investiga tion was therefore conducted to establish a validated assay for perill yl alcohol and its active metabolites in plasma and to characterize th e pharmacokinetics of these compounds after the administration of a si ngle oral dose of the drug to beagle dogs. This information was used t o design a dosing regimen for a more comprehensive toxicological evalu ation of perillyl alcohol from which the starting dose for phase 1 cli nical trials will be established.(2)