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The role of maternal toxicity in lovastatin-induced developmental toxicity.
Birth Defects Res B Dev Reprod Toxicol. 2004 Jun; 71(3):111-23.BD

Abstract

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake.

Authors+Show Affiliations

Merck Research Laboratories, West Point, Pennsylvania 19486, USA. george_lankas@merck.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15282732

Citation

Lankas, George R., et al. "The Role of Maternal Toxicity in Lovastatin-induced Developmental Toxicity." Birth Defects Research. Part B, Developmental and Reproductive Toxicology, vol. 71, no. 3, 2004, pp. 111-23.
Lankas GR, Cukierski MA, Wise LD. The role of maternal toxicity in lovastatin-induced developmental toxicity. Birth Defects Res B Dev Reprod Toxicol. 2004;71(3):111-23.
Lankas, G. R., Cukierski, M. A., & Wise, L. D. (2004). The role of maternal toxicity in lovastatin-induced developmental toxicity. Birth Defects Research. Part B, Developmental and Reproductive Toxicology, 71(3), 111-23.
Lankas GR, Cukierski MA, Wise LD. The Role of Maternal Toxicity in Lovastatin-induced Developmental Toxicity. Birth Defects Res B Dev Reprod Toxicol. 2004;71(3):111-23. PubMed PMID: 15282732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of maternal toxicity in lovastatin-induced developmental toxicity. AU - Lankas,George R, AU - Cukierski,Mark A, AU - Wise,L David, PY - 2004/7/30/pubmed PY - 2005/1/14/medline PY - 2004/7/30/entrez SP - 111 EP - 23 JF - Birth defects research. Part B, Developmental and reproductive toxicology JO - Birth Defects Res B Dev Reprod Toxicol VL - 71 IS - 3 N2 - The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake. SN - 1542-9733 UR - https://www.unboundmedicine.com/medline/citation/15282732/The_role_of_maternal_toxicity_in_lovastatin_induced_developmental_toxicity_ L2 - https://doi.org/10.1002/bdrb.20005 DB - PRIME DP - Unbound Medicine ER -