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Journal of Lipid Research, Vol 29, 43-51, Copyright © 1988 by Lipid Research, Inc.
TA Miettinen
Ketoconazole, an antifungal antibiotic, inhibits cholesterol synthesis by
blocking demethylation of lanosterol. Effects of this inhibition were
studied on serum cholesterol, lipoproteins and cholesterol precursors,
biliary lipid composition, and fecal steroid elimination in five patients
with prostate cancer treated with large doses of ketoconazole. The serum
level of total cholesterol fell by 27%, that of LDL cholesterol by 41% and
that of LDL apoB by 32% with ketoconazole alone; the fall in the total
cholesterol level of a patient treated with ketoconazole-cholestyramine was
65%. Serum contents of free lanosterol and dihydrolanosterol increased up
to 250 times, yet the total concentrations remained less than 2 mg/dl. Of
the other cholesterol precursor sterols only those with delta 8-double bond
increased several times, indicating that in addition to 14 alpha-
demethylation, ketoconazole also interfered with metabolism of later
intermediary sterols to some extent. Compared with serum sterols,
lanosterols were enriched in biliary and fecal sterols up to 10-20 times.
Fecal lanosterol output increased from 12 to 247 mg/day, and comprised over
20% fecal steroids of endogenous origin. Bile acid synthesis was
significantly decreased, the proportion of chenodeoxycholic acid being
markedly reduced in both biliary and fecal bile acids. Cholesterol
absorption appeared to decrease yet fecal neutral sterol output and
cholesterol synthesis were unchanged and the overall sterol synthesis was
increased. It thus appears that ketoconazole inhibits cholesterol
elimination as bile acids. However, by blocking 14 alpha-demethylation, it
results in effective drainage of sterol nucleus as lanosterols into bile
and feces, which, in turn, is associated with a marked reduction in low
density lipoprotein (LDL) cholesterol level probably through activation of
hepatic LDL apoB receptors.
ARTICLES
Cholesterol metabolism during ketoconazole treatment in man
Second Department of Medicine, University of Helsinki, Finland.
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