title: Ketoconazole-induced hepatic lysosomal phospholipidosis: the effect of concurrent barbiturate treatment.
abstract: 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.
authors.affiliation: Health Protection Branch, Bureau of Drug Research, Drug Toxicology Division, Ottawa, Ontario, Canada.
authors.forename: A P
authors.initials: AP
authors.lastname: Pakuts
authors.forename: R J
authors.initials: RJ
authors.lastname: Parks
authors.forename: C J
authors.initials: CJ
authors.lastname: Paul
authors.forename: S J
authors.initials: SJ
authors.lastname: Bujaki
authors.forename: R W
authors.initials: RW
authors.lastname: Mueller
mesh_terms: 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
chemical_list: D001463:Barbiturates; D010743:Phospholipids; D006899:Mixed Function Oxygenases; D007654:Ketoconazole