Ketoconazole-induced hepatic lysosomal phospholipidosis: the effect of concurrent barbiturate treatment.
An unusual hepatic phospholipidosis produced by repeated high doses of ketoconazole in the mouse was investigated. This abnormal phospholipid accumulation was dose dependent after seven days of daily oral treatment over a 150-350 mg/kg ketoconazole dose range. The accumulation continued after 21 days at the 250 mg/kg dose level. Ultrastructural and biochemical studies revealed that ketoconazole produced a hepatic lysosomal accumulation of concentric lamellar bodies, as typically produced by many cationic amphiphilic drugs. Ketoconazole administered orally in mice at 250 mg/kg also induced total hepatic protein, microsomal protein, cytochrome p-450, and ethylmorphine N-demethylation. Concurrent phenobarbital and ketoconazole administration appeared to further increase hepatic drug metabolizing parameters and to reduce the extent of the hepatic phospholipid accumulation.
Pakuts
A P
AP
Health Protection Branch, Bureau of Drug Research, Drug Toxicology Division, Ottawa, Ontario, Canada.
Parks
R J
RJ
Paul
C J
CJ
Bujaki
S J
SJ
Mueller
R W
RW
D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D001463:Barbiturates; D010743:Phospholipids; D006899:Mixed Function Oxygenases; D007654:Ketoconazole