Studies on the effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on the rodent forestomach

The role of maternal toxicity in lovastatin‐induced developmental toxicity

“…It was hypothesized that the observed developmental abnormalities induced in rats by high dosages of lovastatin are secondary to the marked maternal toxicity that is produced early in gestation. Since this maternal toxicity is primarily due to the well-characterized, pharmacologically mediated effect of statins on the rat nonglandular stomach (Kloss et al, 1991) that is readily reversible with mevalonate, this hypothesis is consistent with the original observation of reversibility of the fetal abnormalities by mevalonate coadministration. The results of new developmental toxicity and toxicokinetic studies in rats with lovastatin and L-154819 designed to test this alternate hypothesis are presented.…”

The role of maternal toxicity in lovastatin‐induced developmental toxicity

“…It was hypothesized that the observed developmental abnormalities induced in rats by high dosages of lovastatin are secondary to the marked maternal toxicity that is produced early in gestation. Since this maternal toxicity is primarily due to the well-characterized, pharmacologically mediated effect of statins on the rat nonglandular stomach (Kloss et al, 1991) that is readily reversible with mevalonate, this hypothesis is consistent with the original observation of reversibility of the fetal abnormalities by mevalonate coadministration. The results of new developmental toxicity and toxicokinetic studies in rats with lovastatin and L-154819 designed to test this alternate hypothesis are presented.…”

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

“…While the cellular mechanism of this effect with these enzyme inhibitors has not been identified, it is clearly related to the desired biochemical effect of these agents, as structurally similar compounds with no biochemical activity against HMG-CoA reductase do not produce this effect. As with BHA, there is a clear threshold below which these effects are not observed (58). The abservations that these changes are related to the biochemical effect of the drug and exhibit a clear threshold and that no similar proliferative lesions are seen in other regions of the gastrointestinal tract support the conclusion that these effects observed in rodents do not imply human risk.…”

Subacute Toxicity of a Halogenated Pyrrole Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor in Wistar Rats

“…Parenteral administration of a pharmacologically active form of simvastatin in rodents produced no forestomach hyperplasia or acanthosis at doses that caused such changes when simvastatin was administered by gavage (4). Physical contact may cause sufficient irritation to induce hyperkeratosis, or physical contact may be necessary to achieve high local drug concentrations resulting in pharmacologically mediated changes in gastric and esophageal tissues (6). There is evidence FIG.…”

The role of maternal toxicity in lovastatin‐induced developmental toxicity

“…It was hypothesized that the observed developmental abnormalities induced in rats by high dosages of lovastatin are secondary to the marked maternal toxicity that is produced early in gestation. Since this maternal toxicity is primarily due to the well-characterized, pharmacologically mediated effect of statins on the rat nonglandular stomach (Kloss et al, 1991) that is readily reversible with mevalonate, this hypothesis is consistent with the original observation of reversibility of the fetal abnormalities by mevalonate coadministration. The results of new developmental toxicity and toxicokinetic studies in rats with lovastatin and L-154819 designed to test this alternate hypothesis are presented.…”

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

“…While the cellular mechanism of this effect with these enzyme inhibitors has not been identified, it is clearly related to the desired biochemical effect of these agents, as structurally similar compounds with no biochemical activity against HMG-CoA reductase do not produce this effect. As with BHA, there is a clear threshold below which these effects are not observed (58). The abservations that these changes are related to the biochemical effect of the drug and exhibit a clear threshold and that no similar proliferative lesions are seen in other regions of the gastrointestinal tract support the conclusion that these effects observed in rodents do not imply human risk.…”

Subacute Toxicity of a Halogenated Pyrrole Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor in Wistar Rats

“…Parenteral administration of a pharmacologically active form of simvastatin in rodents produced no forestomach hyperplasia or acanthosis at doses that caused such changes when simvastatin was administered by gavage (4). Physical contact may cause sufficient irritation to induce hyperkeratosis, or physical contact may be necessary to achieve high local drug concentrations resulting in pharmacologically mediated changes in gastric and esophageal tissues (6). There is evidence FIG.…”

The role of maternal toxicity in lovastatin‐induced developmental toxicity

“…It was hypothesized that the observed developmental abnormalities induced in rats by high dosages of lovastatin are secondary to the marked maternal toxicity that is produced early in gestation. Since this maternal toxicity is primarily due to the well-characterized, pharmacologically mediated effect of statins on the rat nonglandular stomach (Kloss et al, 1991) that is readily reversible with mevalonate, this hypothesis is consistent with the original observation of reversibility of the fetal abnormalities by mevalonate coadministration. The results of new developmental toxicity and toxicokinetic studies in rats with lovastatin and L-154819 designed to test this alternate hypothesis are presented.…”

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

“…While the cellular mechanism of this effect with these enzyme inhibitors has not been identified, it is clearly related to the desired biochemical effect of these agents, as structurally similar compounds with no biochemical activity against HMG-CoA reductase do not produce this effect. As with BHA, there is a clear threshold below which these effects are not observed (58). The abservations that these changes are related to the biochemical effect of the drug and exhibit a clear threshold and that no similar proliferative lesions are seen in other regions of the gastrointestinal tract support the conclusion that these effects observed in rodents do not imply human risk.…”

Subacute Toxicity of a Halogenated Pyrrole Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor in Wistar Rats

“…Parenteral administration of a pharmacologically active form of simvastatin in rodents produced no forestomach hyperplasia or acanthosis at doses that caused such changes when simvastatin was administered by gavage (4). Physical contact may cause sufficient irritation to induce hyperkeratosis, or physical contact may be necessary to achieve high local drug concentrations resulting in pharmacologically mediated changes in gastric and esophageal tissues (6). There is evidence FIG.…”