Pharmacokinetics of active drug metabolites after oral administration of perillyl alcohol, an investigational antineoplastic agent, to the dog.
The monocyclic terpene d-limonene, a major component in many citrus essential oils (1-3), has been used for many years as a flavoring agent, food additive, and fragrance (1, 2). It was recently demonstrated that limonene exhibits both chemopreventive and therapeutic effects against chemically induced mammary tumors in rats (4-10). Mechanistic studies revealed that limonene inhibits the posttranslational isoprenylation of 21-26 kDa cellular proteins implicated in cell growth and proliferation (11-13). Limonene is extensively metabolized by a variety of mammalian species (14-17). Its principal circulating metabolites identified in the rat, perillic acid and dihydroperillic acid, are also effective inhibitors of isoprenylation and cellular proliferation in vitro (17, 18). Furthermore, one of the metabolic precursors of these compounds, perillyl alcohol (16), is considerably more potent than limonene against the in vivo rat mammary tumor models (19). A preliminary report of an ongoing phase I clinical trial with limonene indicated that a single oral dose of 100 mg/kg is well tolerated (20). However, an extrapolation 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 problems. Thus, perillyl alcohol is currently being developed as a clinical candidate at the National Cancer Institute because of its greater potency than limonene, which may enable potentially effective systemic concentrations of the active principals to be achieved at considerably lower doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Phillips
L R
LR
Laboratory of Pharmaceutical Chemistry, National Cancer Institute, Frederick, MD 21701-8572, USA.
Malspeis
L
L
Supko
J G
JG
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D039821:Monoterpenes; D013729:Terpenes / Q000097:blood / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D039821:Monoterpenes; D013729:Terpenes; C032208:perillyl alcohol