Embryotoxicity studies of norfloxacin in cynomolgus monkeys. II. Role of progesterone

Abstract

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.

Frequency of prenatal loss in a macaque breeding colony

“…Experimental evidence to support these findings has been provided by studies with antimicrobials, the fluoroquinolones, which have been shown to increase the incidence of abortion in cynomolgus macaques when administered between GD 20 and 34 [Cukierski et al, 1989[Cukierski et al, , 1992Hummler et al, 19931. Suppression of trophoblastic production of progesterone was associated with early abortions induced by norfloxacin, the most developmentally toxic of the four f luoroquinolones studied.…”

The safety of quinolones and fluoroquinolones in pregnancy: a meta‐analysis

“…There are several possible theories why quinolones can potentially increase the risk for miscarriage. 33 It should be noted, however, that most of these complications were witnessed only following the administration of very high doses, and were dependent on the specific antibiotic examined. This can explain the results only to some extent, as subanalysis of the studies that compared quinolones with different antibiotics versus no treatment resulted in similar results.…”

“…[9][10][11]30,31 Suggested mechanisms for these complications include single-strand DNA breaks, the inhibition of chondrocyte proliferation, 32 and a reduction in placental-derived progesterone production. 33 It should be noted, however, that most of these complications were witnessed only following the administration of very high doses, and were dependent on the specific antibiotic examined. The third theory may be that the appointment for the condition requiring quinolone therapy itself led to an earlier diagnosis of pregnancy, and that the risk of miscarriage decreases with advancing gestational age.…”

Developmental Toxicity Studies of the Quinolone Antibacterial Agent Irloxacin in Rats and Rabbits

“…The induction of embryotoxic effects (e.g. embryonic loss, decreased fetal weight, retardation of ossification, and/or increased incidence of skeletal variations) in one or more laboratory animal species has been a common finding with fluoroquinolones like norfloxacin [5], ofloxacin [6], ciprofloxacin [7], pefloxacin [8], and levofloxacin [9]. No teratological effects have been observed with these compounds and the described embryotoxic effects have generally been considered to be secondary to maternal toxic effects after high dose administration.…”