Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The toxicity of a fluorinated-biphenyl HMG-CoA reductase inhibitor in beagle dogs. 205 62

The administration of high dosages of various hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors has resulted in the development of subcapsular lenticular opacities in dogs. While dogs receiving cataractogenic doses of HMG-CoA reductase inhibitors experienced profound decreases in circulating serum cholesterol concentrations (40-60% reductions in total serum cholesterol), a causal relationship between serum cholesterol lowering and cataractogenesis was not established. A strong relationship was demonstrated, however, between the systemic exposure to inhibitor (plasma drug levels) and the cataractogenic potential of the various compounds studied. Analysis of lenses from dogs chronically dosed with various HMG-CoA reductase inhibitors revealed the presence of low drug levels in the lens (less than 500 ng equivalents g-1), but no correlation was observed between the amount of drug associated with the lens after chronic treatment and cataract development. In addition, no abnormalities in cholesterol content or sterol composition were observed in clear and/or cataract containing lenses from dogs chronically dosed with HMG-CoA reductase inhibitors. The kinetics of drug appearance in the aqueous and lens cortex was assessed after doses of various HMG-CoA reductase inhibitors, and suggested somewhat higher but not statistically significant peak concentrations of inhibitor were achieved by compounds which produced a higher incidence of cataracts. These data have suggested that high doses of HMG-CoA reductase inhibitors may increase lenticular exposure to drug via the aqueous humor by producing a substantial systemic exposure to drug substance. This may result in an increased concentration of inhibitor in the outer cortical region of the lens where cholesterol synthesis is critical, thereby resulting in the development of opacities. The production of lenticular changes by a HMG-CoA reductase inhibitor of diverse chemical structure establishes, with reasonable assurance, that these lens changes are mechanism based (i.e. a product of the biochemical mechanism of action of this class of compounds). An extrapolation of these findings to patients receiving therapeutic dosages enables a favorable risk evaluation since the doses to be employed clinically are much lower and result in a far lower systemic exposure to drug substance.
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PMID:On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors. 230 97

Simvastatin, a hydroxy-methylglutaryl-coenzyme A reductase inhibitor intended for use as a hypocholesterolemic agent, has undergone a thorough preclinical toxicology evaluation. This review describes preclinical toxicology findings associated with simvastatin administration in animals and provides the rationale for our conclusion that these changes are not indicative of potential human toxicity. Although it was not surprising to find that a potent inhibitor of this key biochemical pathway produces toxicity at high dosages in animals, none of the observed changes poses a significant risk to humans at clinical dosages. Many of the toxicities produced by high dosage levels of simvastatin in animals are directly related to the drug's biochemical mechanism of action and are the result of a profound, sustained inhibition of the target enzyme that is not anticipated at clinical dosages. Furthermore, several of the simvastatin-induced changes are species-specific responses to this agent and are not relevant to human risk assessment. Of the treatment-related changes reported for simvastatin, the development of cataracts in dogs has received considerable attention. The available data demonstrate a wide margin of safety in terms of dosage levels required to elicit this response as well as the plasma concentrations associated with the development of these ocular lesions. The data suggest that the development of lenticular opacities at clinical doses of simvastatin is highly improbable. Overall, simvastatin is highly improbable. Overall, simvastatin was well-tolerated by animals in preclinical toxicology studies, and no findings contraindicating its use in humans were identified.
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PMID:Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. 267 82

Cerivastatin is a new but structurally distinct 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin"). It effectively decreases low-density lipoprotein (LDL) cholesterol at 1% of the doses of other currently available statins. The toxicology of cerivastatin was evaluated in a comprehensive program of studies including: (1) single- and multiple-dose toxicity studies in rats, mice, minipigs, dogs, and monkeys; (2) reproductive toxicity studies in rats and rabbits; (3) in vitro and in vivo mutagenicity assays in rats and mice; and (4) carcinogenicity studies in rats and mice. In addition, studies were undertaken to investigate the effects of cerivastatin on lens opacity, testicular tissue, and hemorrhage in dogs. Oral administration of single and multiple doses of cerivastatin over periods ranging from 4 weeks to 24 months was generally well tolerated. Adverse effects were similar to those observed with other statins and primarily involved the liver and muscle tissue. At the high doses used in the toxicologic studies, cerivastatin caused elevations in serum transaminases and creatine phosphokinase levels as well as some degeneration of muscle fibers in rats, mice, dogs, and minipigs. In dogs, the species most sensitive to statins, cerivastatin caused erosions and hemorrhages in the gastrointestinal tract, bleeding in the brain stem with fibroid degeneration of vessel walls in the choroid plexus, and lens opacity. Apart from minor morphologic changes in the testicular tissue of dogs--the only organ for which a comparably low margin of safety was observed--cerivastatin had no significant effects on the male or female reproductive system. Cerivastatin also caused no primary embryotoxic or teratogenic effects. With the exception of cerivastatin-induced effects on the eyes and testicles, administration of mevalonic acid reversed the toxicologic effects of cerivastatin, indicating that the toxic effects were related to its mode of action and not to any intrinsic toxicity of the molecule itself. There was no evidence that cerivastatin had any mutagenic effects and, in contrast to other statins, high doses of cerivastatin did not induce tumors in rats. The main metabolite of cerivastatin was well tolerated systemically in all animals, including dogs. Overall, cerivastatin has a similar toxicologic profile to other statins and is a well-tolerated HMG-CoA reductase inhibitor.
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PMID:Preclinical safety evaluation of cerivastatin, a novel HMG-CoA reductase inhibitor. 973 41