The toxicity of a fluorinated-biphenyl HMG-CoA reductase inhibitor in beagle dogs.
L-645, 164, a potent inhibitor of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase, is a structurally unique, synthetic monofluorinated-biphenyl that was administered to beagle dogs at dosages of 2, 10, or 50 mg/kg/day for 14 weeks to evaluate its toxic potential. Previously tested HMG-CoA reductase inhibitors from this laboratory have either been semisynthetic or fermentation-derived products containing a hexahydronaphthalene ring structure (i.e., lovastatin and simvastatin). Administration of L-645, 164 produced a significant spectrum of lesions, some of which have been previously associated with compounds of this pharmacological class, while others were unique to this monofluorinated-biphenyl inhibitor. Subcapsular lenticular opacities were produced in six of eight of the dogs receiving 50 mg/kg/day of L-645, 164 within 8 weeks of dosing. One dog receiving this dosage level experienced increases in serum alanine aminotransferase activity to levels 10 times those in concurrent control dogs. Light and electron microscopy of a wedge biopsy obtained within 3 days of this transaminase elevation failed to reveal any significant changes and the elevation resolved spontaneously despite continued drug administration. Lesions of the optic nerve and acoustic-vestibular tract and trapezoid decussation were observed in several dogs receiving 50 mg/kg/day. In addition, similar changes were observed in the optic tract in several of the dogs receiving 50 mg/kg/day and in one dog receiving 2 mg/kg/day of L-645,164. These were unique to L-645,164 and have not been observed after the administration of other HMG-CoA reductase inhibitors in this laboratory. Optic tract changes were generally mild, consisting of small to medium vacuoles without apparent myelin loss. Lesions in the other areas ranged from very slight to prominent vacuolation. No clinical signs were observed. Peak plasma drug levels of L-645,164 at 50 mg/kg were greater than 5 micrograms/ml, about one order of magnitude greater than those attained after administration of pharmacologically equipotent doses of lovastatin and simvastatin. These findings support previous observations that HMG-CoA reductase inhibitors producing high plasma drug levels are associated with a significant degree of systemic toxicity. In addition, the drug-induced CNS lesions attributed to L-645,164 appear also to be related to its chemical structure since similar lesions have not been observed after the administration of other structurally unrelated HMG-CoA reductase inhibitors that produce high plasma drug concentrations and comparable degrees of serum cholesterol lowering.
Gerson
R J
RJ
Merck Sharp and Dohme Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486.
Allen
H L
HL
Lankas
G R
GR
MacDonald
J S
JS
Alberts
A W
AW
Bokelman
D L
DL
D000818:Animals; D001713:Biphenyl Compounds / Q000097:blood / Q000633:toxicity*; D001921:Brain / Q000473:pathology; D002386:Cataract / Q000139:chemically induced; D004285:Dogs; D005704:Gallbladder / Q000187:drug effects / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006965:Hyperplasia / Q000139:chemically induced; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects; D015394:Molecular Structure; D009092:Mucous Membrane / Q000187:drug effects / Q000473:pathology; D011753:Pyrones / Q000097:blood / Q000633:toxicity*; D012871:Skin Diseases / Q000139:chemically induced
D001713:Biphenyl Compounds; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011753:Pyrones; C063286:L 645164