Embryotoxicity studies of norfloxacin in cynomolgus monkeys. II. Role of progesterone.
Norfloxacin, an orally active fluoroquinolone antimicrobial, has been reported to be embryolethal but not teratogenic when administered to pregnant cynomolgus macaques prior to gestational day (GD) 36 at doses > or = 200 mg/kg/day. Additional studies have been performed in an effort to examine the mechanism responsible for this effect, particularly regarding the role of progesterone (P). The first study (Study I) investigated the effect of norfloxacin administration during early pregnancy (200 mg/kg/day; daily GD 20-30) in the absence of a functional corpus luteum (CL). The CL was surgically removed from 16 gravid females on GD 19 in order to focus on placental-derived P; ten were dosed with norfloxacin and six received vehicle only. Embryolethality was observed for 7/10 (70%) of the treated animals during GD 25-31 versus 0/6 (0%) for controls. A reduction in serum P was noted prior to embryonic loss, although no significant effects on chorionic gonadotropin (CG), 17 beta-estradiol (E2), or P or E urinary metabolites were observed. A second study (Study II) was performed in order to evaluate the capacity of norfloxacin (200 mg/kg) to reduce CL-derived P in both normally cycling and CG-stimulated nonpregnant females (ten treated, ten controls; daily for 8 days). No effects on P production or on luteal phase or menstrual cycle lengths were observed. The third study (Study III) was designed to examine the effect of norfloxacin on the metabolism and excretion of P in nonpregnant females. Silastic P implants were placed subcutaneously in order to maintain constant P levels during a 10 day treatment regimen (200 mg/kg/day; ten controls, nine treated). Five of the controls and four of the norfloxacin-treated females also received 14C-P intravenously within 1 hr of the last dose of norfloxacin in order to study excretory patterns. No significant differences between control and treated groups were observed. The results of these studies combined suggest that the developmental toxic effects observed in prior studies and Study I are specific to pregnancy and directly related to placental-derived P production.
Cukierski
M A
MA
California Primate Research Center, University of California, Davis 95617.
Hendrickx
A G
AG
Prahalada
S
S
Tarantal
A F
AF
Hess
D L
DL
Lasley
B L
BL
Peter
C P
CP
Tarara
R
R
Robertson
R T
RT
D000818:Animals; D006063:Chorionic Gonadotropin / Q000378:metabolism; D003338:Corpus Luteum / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005313:Fetal Death / Q000139:chemically induced* / Q000378:metabolism; D005865:Gestational Age; D008252:Macaca fascicularis; D009643:Norfloxacin / Q000633:toxicity*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D011374:Progesterone; D004958:Estradiol; D009643:Norfloxacin