668 M.A. Huestis
ance of these polar metabolites is low due to extensive protein binding (Hunt and
Jones 1980). No significant differences in metabolism between men and women
have been reported (Wall et al. 1983).
After the initial distribution phase, the rate-limiting step in the metabolism of
THC is its redistribution from lipid depots into blood (Garrett and Hunt 1977).
Lemberger et al. suggested that frequent cannabis smoking could induce THC
metabolism (Lemberger et al. 1971). However, later studies did not replicate this
finding (Agurell et al. 1986; Harvey and Paton 1986).
2.3.2
Extrahepatic Metabolism
Other tissues, including brain, intestine, and lung, may contribute to the
metabolismofTHC,althoughalternatehydroxylationpathwaysmaybemore
prominent (Ben-Zvi et al. 1976; Greene and Saunders 1974; Krishna and Klotz
1994; Watanabe et al. 1988; Widman et al. 1975). An extrahepatic metabolic site
should be suspected whenever total body clearance exceeds blood flow to the liver,
or if severe liver dysfunction does not affect metabolic clearance (Krishna and
Klotz 1994). Of the ten mammalian classes of cytochrome P450 systems, the cy-
tochrome 1, 2, 3, and 4 families primarily metabolize xenobiotics and are found
in the liver, small intestine, peripheral blood, bone marrow, and mast cells in de-
creasing concentrations, with the lowest concentrations in the brain, pancreas, gall
bladder, kidney, skin, salivary glands, and testes. Within the brain, higher concen-
trations of cytochrome P450 enzymes are found in the brain stem and cerebellum
(Krishna and Klotz 1994). The hydrolyzing enzymes, non-specific esterases,β-
glucuronidases, and sulfatases, are primarily found in the gastrointestinal tract.
Side chain hydroxylation of THC is prominent in THC metabolism by the lung.
Metabolism of THC by fresh biopsies of human intestinal mucosa yielded polar
hydroxylated metabolites that directly correlated with time and the amount of
intestinal tissue (Greene and Saunders 1974).
In a study of the metabolism of THC in the brains of mice, rats, guinea pigs, and
rabbits, Watanabe et al. found that brain microsomes oxidized THC to monohy-
droxylated metabolites (Watanabe et al. 1988). Hydroxylation of C4 of the pentyl
side chain produced the most common THC metabolite in the brains of these
animals, similar to THC metabolites produced in the lung. These metabolites are
pharmacologically active, but their relative activity is unknown.
2.4
Elimination
Within 5 days, a total of 80% to 90% of a THC dose is excreted, mostly as hydrox-
ylated and carboxylated metabolites (Halldin et al. 1982; Harvey 2001). More than
65% is excreted in the feces, with approximately 20% eliminated in the urine (Wall
et al. 1983). Numerous acidic metabolites are found in the urine, many of which