Developmental toxicity of 4-substituted amphetamines in mice.

Despite overwhelming and tragic evidence of their detrimental and dangerous consequences, amphetamines remain significant drugs of abuse and addiction. The effects of 4-substituted amphetamines: 4-hydroxyamphetamine (4-HA), 4-methoxyamphetamine (4-MEA), 4-ethoxyamphetamine (4-ETA), 4-propoxyamphetamine (4-PPA), and 4-benzyloxyamphetamine (4-BEA) on intrauterine development, pregnancy outcome, postnatal growth, and survival were compared in Swiss-Webster mice. Single daily doses (0, 50, or 100 mg/kg) of an aqueous solution of different amphetamines were administered on pregnancy days 6 through 18. The 50 mg/kg doses of all amphetamines were well tolerated by the mothers and did not produce any overt signs of maternal toxicity or death. However, a few mothers died on different days of gestation after receiving 100 mg/kg of 4-HA, 4-MEA, 4-ETA, and 4-BEA. The mothers that failed to deliver naturally (3 d after the due date) were killed and their uteri were examined for live/dead fetuses and resorption sites. In comparison with respective controls, the incidence of resorptions was markedly higher in the 4-MEA- and 4-ETA-dosed groups. Delivery was prolonged in the 4-PPA- and 4-BEA-treated dams. Apparently well-formed but dead pups were delivered by 4-HA-, 4-PPA-, and 4-BEA-dosed mice. Marked reductions in average litter size and weight occurred after intrauterine exposure to 100 mg/kg 4-BEA. Treatment with 4-ETA, 4-PPA, and 4-BEA not only resulted in a high incidence of cannibalism within 24 h after birth but also caused an increase in cumulative pup mortality during the first 3 weeks of age. Body weight gain was significantly lower in 3-week-old offspring exposed to 4-HA and 4-PPA than in the controls. The findings suggest that 4-substituted amphetamines exhibit a wide variation in their effects on maternal toxicity and pregnancy wastage, and produce adverse effects on parturition, pup survival, and postnatal development.

Effect of ciprofloxacin on the disposition of 14C-dideoxyinosine-derived radioactivity in the rat.

The potential for the antibacterial agent ciprofloxacin to interfere with the disposition of the antiviral agent dideoxyinosine (ddI) was evaluated in adult male Wistar rats. The combination group (n = 10) was dosed orally with 100 mg/kg ciprofloxacin in water every 12 h for three consecutive doses. Thirty minutes after the last dose, a bolus IV injection of 50 mg/kg 14C-ddI in physiologic saline was given over 7-10 sec through the penile vein. The control group (n = 8) received a single dose of IV 14C-ddI. Blood, urine and fecal samples were collected from 0-4 h, and tissue samples were removed at 4 h after ddI administration. The disappearance of 14C from blood followed the kinetics of a two-compartment model with bolus input and first-order output. The following pharmacokinetic parameters (mean +/- SD) were calculated based on total blood radioactivity for the 14C-ddI alone and combination groups, respectively: blood clearance 13.5 +/- 2.0 vs. 12.7 +/- 1.5 ml/min/kg, terminal disposition half-life 49.9 +/- 2.2 vs. 49.0 +/- 6.0 min, steady-state volume of distribution 891 +/- 134 vs. 825 +/- 126 ml/kg, mean residence time 66.2 +/- 3.1 vs. 65.0 +/- 7.8 min (the power to detect a 20% decrease in the above parameters, relative to the reference ddI alone, was > 85% at the 5% significance level), percentage of administered dose recovered in urine 62.2 +/- 9.8% vs. 56.6 +/- 13.0%. Most of the radioactivity in tissues was concentrated in the liver, adrenal, spleen and kidney. Except for significant decreases (p < 0.05) in the levels of 14C in skeletal muscle and cecum of combination treated rats, the coadministration of ciprofloxacin showed no differences in either the tissue levels of 14C or the pharmacokinetic parameters of 14C-ddI-derived radioactivity. The results obtained with total 14C measurements suggest that ciprofloxacin does not alter the disposition of ddI in the rat, although unchanged ddI was not determined.

Transplacental and mammary passage of radioactivity in rats treated vaginally and orally with [14C]propranolol.

The milk transfer, maternal-fetal distribution, and disposition of the antihypertensive/spermicidal agent propranolol were studied in pregnant and lactating rats. Single doses (10 mg/kg) of an aqueous solution of [14C]propranolol were administered either orally (po) or intravaginally (ivg) on gestational d 15, or on postpartum d 7-10. Upon ivg administration, [14C]propranolol was quickly transferred to systemic circulation and the mean blood [14C] concentrations were significantly greater during the first 0.25-2 h than in po dosed counterparts. About 98% of the ivg applied dose was absorbed after 6 h in gravid rats, and the combined 6-h excretions of radioactivity in the urine (ivg = 24.6%; po = 22.9%) and feces (ivg = 16.8%; po = 14.6%) were equivalent in both groups. At the end of 6 h, the levels of [14C] in the urinary bladder, adrenal, uterus, ovary, spleen, skeletal muscle, brain, heart, lung and fat were significantly higher in ivg treated rats than po dosed animals. Compared with the maternal plasma (ivg = 0.76; po = 0.88 microgram/ml), the mean concentrations of [14C] in the placentas were similar in both groups, while the amounts of [14C] were three to five times lower in the amniotic fluids and the fetuses of both po and ivg treated dams. In lactating rats, over 99% of the administered radioactivity was absorbed from the vagina within 6 h. The blood concentrations of [14C] were significantly elevated at 0.5 and 1 h in the per vaginam treated animals, and afterward the disappearance rate of [14C] followed a similar course in both groups. Following ivg application, the milk radioactivity peaked at 0.5 h and declined rapidly. However, the appearance of [14C] in milk was rather slow after oral dosing: the milk [14C] peaked between 2 and 3 h posttreatment and remained steady thereafter. The milk to blood (M/B) [14C] concentration ratios were markedly greater during 0.5 to 1 h in the ivg group than in their po dosed counterparts. At 6 h, the [14C] levels in the whole blood, plasma, milk, and mammary gland were virtually equivalent in the ivg and po treated females. Comparison of the areas under the milk [14C] concentration-time curves (AUCs) indicated that the milk availability of [14C] was about 31% more in dams dosed vaginally. These data suggest that route of administration alters the disposition and milk excretion of [14C]propranolol-derived radioactivity in pregnant and lactating rats.

Pre- and postnatal development of rats following concomitant intrauterine exposure to propoxyphene and chlordiazepoxide.

The pre- and postnatal effects of the combined oral administration of propoxyphene (PPX, 100 mg/kg/day) and chlordiazepoxide (CDX, 25, 50 or 100 mg/kg/day) were evaluated in Wistar rats in separate experiments by dosing on days 6 through 21 of pregnancy. The controls were given either an aqueous gum tragacanth solution or PPX alone. Maternal toxicity, as evident from death or reduction in body weight, was observed in dams given PPX + 100 mg/kg/day CDX, although previous studies with CDX alone showed no maternal toxicity [5]. PPX alone was well tolerated by the mothers and produced neither any detrimental effects on litter size, litter or pup weights, nor any visceral or skeletal anomalies. Treatment with the two largest doses of CDX + PPX was associated with a high incidence of resorptions, a significant reduction in fetal weight, increased incidence of runts, retarded ossification of skull bones, and a variety of sternal defects. In the postnatal study, PPX alone did not affect pup survival or growth, whereas the combined dosing of PPX and CDX resulted in delayed delivery, increase in stillbirths, reduction in birth weight and a high neonatal mortality compared to pups in the control groups. Pentobarbital sleeping time remained unaltered in 11 to 12-week old offspring of dams given PPX alone. However, in 11 to 12-week old progeny exposed in utero to 25 mg/kg CDX + PPX, the pentobarbital sleeping time was significantly prolonged in males but shortened in females, suggesting that prenatal exposure to PPX + CDX caused a sex-related reversal to pentobarbital hypnosis in mature rats.

The disposition of [14C]metronidazole in rats following vaginal and oral administration.

The absorption, tissue distribution and excretion of [17C]metronidazole (14C-MTZ) were compared during the first 4 h after administration of 10 mg kg-1 of 14C-MTZ either orally or intravaginally (i.v.g.) to rats. Peak 14C blood concentrations were reached at 1 h in both groups. Blood samples collected at 0.5, 3 and 4 h had a higher 14C concentration in orally dosed rats (P less than 0.05) than in i.v.g.-treated animals. About 3% of the i.v.g. applied dose remained in the vagina at 4 h. After 4 h, the plasma, liver, kidney, brain, lung and uterus concentrations of 14C were similar in both groups, whereas the blood, skeletal muscle and fat 14C values were significantly greater in the orally dosed rats. The total recoveries of 14C in the urine and faeces did not differ (ca 38% over 4 h) between the two groups. These results suggest that the kinetics of metronidazole are similar after the administration of equal amounts of this drug by either route.

Effect of isoniazid on the metabolism of 14C-diphenylhydantoin in rats.

The effect of isoniazid (INH, 0,5, 10 or 20 mg/kg; p.o.) on the metabolic disposition of 14C-diphenylhydantoin (DPH, 50 mg/kg; i.v.) was studied in rats for 5 hours. The disappearance rate of 14C from the blood was similar up to 2 hr, whereas at 3 hr the levels of 14C were significantly higher in 10 and 20 mg/kg INH-treated rats than the controls. While the urinary excretion remained virtually unaltered, the fecal excretion of 14C was significantly reduced in the presence of INH. Increasing doses of INH caused a corresponding increase in the concentration of 14C in the blood, plasma, liver, kidney, lung, brain, skeletal muscle, fat, heart, tests and spleen. At the end of 5 hr, about 74% of the radioactivity was present as unmetabolized DPH in the plasma of control animals; this was increased significantly in a dose-related manner by INH, reaching a concentration of 93% at the highest doses of INH administered. The results suggest that the INH-induced elevation of DPH-derived 14C in plasma and its marked accumulation in other tissues is due to inhibition of both the p-hydroxylation of DPH and the glucuronidation of its metabolites.