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, D. L. Hess, M. J. Cukierski, Alice F Tarantal, T. Nyland, R. T. Robertson, Andrew 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. L., ... 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, D. L.; Cukierski, M. J.; Tarantal, Alice F; Nyland, T.; Robertson, R. T.; Hendrickx, Andrew 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, DL, 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, D. L. ; Cukierski, M. J. ; Tarantal, Alice F ; Nyland, T. ; Robertson, R. T. ; Hendrickx, Andrew 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.
@article{53d8cf7e765949c7a19dcbbb3792f1d2,
title = "Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys",
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.",
author = "Cukierski, {M. A.} and S. Prahalada and Zacchei, {A. G.} and Peter, {C. P.} and Rodgers, {J. D.} and Hess, {D. L.} and Cukierski, {M. J.} and Tarantal, {Alice F} and T. Nyland and Robertson, {R. T.} and Hendrickx, {Andrew G}",
year = "1989",
language = "English (US)",
volume = "39",
pages = "39--52",
journal = "Teratology",
issn = "1542-0752",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Embryotoxicity studies of norfloxacin in cynomolgus monkeys

T2 - I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys

AU - Cukierski, M. A.

AU - Prahalada, S.

AU - Zacchei, A. G.

AU - Peter, C. P.

AU - Rodgers, J. D.

AU - Hess, D. L.

AU - Cukierski, M. J.

AU - Tarantal, Alice F

AU - Nyland, T.

AU - Robertson, R. T.

AU - Hendrickx, Andrew G

PY - 1989

Y1 - 1989

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0024545415&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024545415&partnerID=8YFLogxK

M3 - Article

C2 - 2718139

AN - SCOPUS:0024545415

VL - 39

SP - 39

EP - 52

JO - Teratology

JF - Teratology

SN - 1542-0752

IS - 1

ER -