Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys

M. A. Cukierski, S. Prahalada, A. G. Zacchei, C. P. Peter, J. D. Rodgers, David Hess, M. J. Cukierski, A. F. Tarantal, T. Nyland, R. T. Robertson, A. G. Hendrickx

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    Norfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential development toxicity. Fifty-seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on range-finding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty-six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10-day periods on GD 36-45, 71-80, or 111-120. There were no maternotoxin, embryotoxic, or fetotoxic effects observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose-proportionate. However, at a given dose, administered in cross-over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (~20-40%) than during pregnancy when the same subject was compared. At the non-observed-effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.

    Original languageEnglish (US)
    Pages (from-to)39-52
    Number of pages14
    JournalTeratology
    Volume39
    Issue number1
    StatePublished - 1989

    Fingerprint

    Teratology
    Norfloxacin
    Macaca fascicularis
    Haplorhini
    Plasmas
    Toxicity
    Pregnancy
    Organogenesis
    Volunteers
    Body Weight
    Mothers
    Anti-Bacterial Agents

    ASJC Scopus subject areas

    • Developmental Biology
    • Health, Toxicology and Mutagenesis
    • Embryology
    • Toxicology

    Cite this

    Cukierski, M. A., Prahalada, S., Zacchei, A. G., Peter, C. P., Rodgers, J. D., Hess, D., ... Hendrickx, A. G. (1989). Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys. Teratology, 39(1), 39-52.

    Embryotoxicity studies of norfloxacin in cynomolgus monkeys : I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys. / Cukierski, M. A.; Prahalada, S.; Zacchei, A. G.; Peter, C. P.; Rodgers, J. D.; Hess, David; Cukierski, M. J.; Tarantal, A. F.; Nyland, T.; Robertson, R. T.; Hendrickx, A. G.

    In: Teratology, Vol. 39, No. 1, 1989, p. 39-52.

    Research output: Contribution to journalArticle

    Cukierski, MA, Prahalada, S, Zacchei, AG, Peter, CP, Rodgers, JD, Hess, D, Cukierski, MJ, Tarantal, AF, Nyland, T, Robertson, RT & Hendrickx, AG 1989, 'Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys', Teratology, vol. 39, no. 1, pp. 39-52.
    Cukierski, M. A. ; Prahalada, S. ; Zacchei, A. G. ; Peter, C. P. ; Rodgers, J. D. ; Hess, David ; Cukierski, M. J. ; Tarantal, A. F. ; Nyland, T. ; Robertson, R. T. ; Hendrickx, A. G. / Embryotoxicity studies of norfloxacin in cynomolgus monkeys : I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys. In: Teratology. 1989 ; Vol. 39, No. 1. pp. 39-52.
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    abstract = "Norfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential development toxicity. Fifty-seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on range-finding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty-six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10-day periods on GD 36-45, 71-80, or 111-120. There were no maternotoxin, embryotoxic, or fetotoxic effects observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose-proportionate. However, at a given dose, administered in cross-over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (~20-40{\%}) than during pregnancy when the same subject was compared. At the non-observed-effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.",
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    AU - Zacchei, A. G.

    AU - Peter, C. P.

    AU - Rodgers, J. D.

    AU - Hess, David

    AU - Cukierski, M. J.

    AU - Tarantal, A. F.

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    AU - Robertson, R. T.

    AU - Hendrickx, A. G.

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