Maternal-fetal distribution of methaqualone in control and SKF 525-A-pretreated pregnant mice

Male mice and pregnant and nonpregnant female mice were pretreated with saline or SKF 525-A (50 mg/kg, ip) and gavaged 1 hr later with [¹⁴C]methaqualone (MTQ) (25 mg/kg). Unchanged [¹⁴C]MTQ was determined in some or all of the following tissues: brain, spinal cord, eye, liver, lung, heart, spleen, kidney, muscle, fat, uterus, plasma, amniotic fluid, placenta, whole fetus, fetal brain, and liver. In saline controls, the MTQ concentrations in most adult tissues, whole fetus, and fetal brain and liver reached peak values at 1.5 hr. The tissue to plasma concentration ratios for fat and uterus were 4.5 and 1.1, respectively; those for other tissues varied from a low of 0.3 for amniotic fluid to a high of 0.8 for liver. At 1.5 hr, the fetal brain and liver contained concentrations of MTQ lower than the corresponding maternal tissues. Except for fat, the amounts in various tissues declined to trace amounts at 24 hr. Brain, plasma, lung, and liver concentrations in males and nonpregnant females were not different from each other but were significantly lower than those in pregnant mice. SKF 525-A pretreatment shifted the peak concentrations of MTQ to 3 hr in most tissues and caused marked tissue elevations.     

Triethylenemelamine: comparative cytogenetic effects induced by oral or parenteral routes of administration in rats

Male mice and pregnant and nonpregnant female mice were pretreated with saline or SKF 525-A (50 mg/kg, ip) and gavaged 1 hr later with [¹⁴C]methaqualone (MTQ) (25 mg/kg). Unchanged [¹⁴C]MTQ was determined in some or all of the following tissues: brain, spinal cord, eye, liver, lung, heart, spleen, kidney, muscle, fat, uterus, plasma, amniotic fluid, placenta, whole fetus, fetal brain, and liver. In saline controls, the MTQ concentrations in most adult tissues, whole fetus, and fetal brain and liver reached peak values at 1.5 hr. The tissue to plasma concentration ratios for fat and uterus were 4.5 and 1.1, respectively; those for other tissues varied from a low of 0.3 for amniotic fluid to a high of 0.8 for liver. At 1.5 hr, the fetal brain and liver contained concentrations of MTQ lower than the corresponding maternal tissues. Except for fat, the amounts in various tissues declined to trace amounts at 24 hr. Brain, plasma, lung, and liver concentrations in males and nonpregnant females were not different from each other but were significantly lower than those in pregnant mice. SKF 525-A pretreatment shifted the peak concentrations of MTQ to 3 hr in most tissues and caused marked tissue elevations.     

Distribution of cocaine and metabolites in the pregnant rat and fetus in a chronic subcutaneous injection model

We examined the distribution of cocaine and its metabolites benzoylecgonine (BE) and norcocaine (NOR) in pregnant Sprague–Dawley rats and fetuses following twice-daily subcutaneous (s.c.) injections of 20 mg/kg cocaine HCl from gestational day (GD) 8 through GD 20. On GD 21, the animals received a single injection and maternal trunk blood, fetal blood, fetal brains, and amniotic fluid were collected 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, or 12 h later for cocaine and metabolite analyses by high-performance liquid chromatography (HPLC) with UV detection. The highest concentrations of cocaine and BE were detected in maternal plasma at 1 h and 4 h respectively. Cocaine peaked at 2 h and BE at 4 h in both fetal plasma and brain. In amniotic fluid, cocaine levels peaked at 2 h, but the highest BE levels were found at 8 h postinjection. An additional group of chronically treated dams was given both cocaine injections on GD 21 and sacrificed 2 h later. Benzoylecgonine concentrations were increased in fetal plasma, fetal brain, and amniotic fluid when compared with the 2-h results following a single cocaine treatment. Moreover, NOR, which had not been previously detected, was now measurable in the amniotic fluid.     

Cocaine-induced hepatotoxicity in mice

Cocaine, 75 mg/kg, ip, produced 53% mortality in male mice and 74% mortality in female mice. All deaths in both groups occurred during the first 3 hr following treatment. Phenobarbital (PB) pretreatment protected against this acute cocaine-induced mortality. However, either PB pretreatment or 3-methylcholanthrene pretreatment produced delayed toxicity characterized by hepatic dysfunction and necrosis. These lesions could not be induced in rats. PB plus cocaine treatment reduced hepatic glutathione concentrations by 40%. PB pretreatment did not alter the plasma concentrations of cocaine plus metabolites, but did increase the accumulation of cocaine plus metabolites in liver tissue. PB plus cocaine treatment produced a dose-related increase in serum glutamic-pyruvic transaminase activity and periportal necrosis. Enhancement of intracellular glutathione concentrations by pretreatment with cysteine protected the liver against cocaine-induced injury. Depletion of intracellular glutathione concentrations by pretreatment with diethylmaleate exaggerated the cocaine-induced injury. Cocaine covalently bound to hepatic protein. PB pretreatment increased by 85% the cocaine covalently bound to hepatic protein. Cocaine was N-dealkylated by hepatic microsomes, and PB pretreatment enhanced hepatic N-dealkylation of cocaine. Cocaine is biotransformed to a chemically reactive intermediate metabolite which produces hepatic dysfunction and periportal necrosis.     

妊娠中晚期接触可卡因对小鼠胎儿神经系统发育的影响

目的　观察妊娠母体接触可卡因引起的胎儿神经系统发育异常 ,研究宫内暴露可卡因引起的胎儿发育迟缓是否与母体孕期营养不良有关以及胎儿神经系统发育异常与神经递质的变化之间的关系。方法　小鼠妊娠d 8(E8)到d 17(E17) ,每日 2次颈背部皮下注射盐酸可卡因 2 0mg·kg-1·d-1,同时建立饮食对照组和盐水对照组 ,每日 2次注射生理盐水 2 0ml·kg-1·d-1,在此期间记录各组母鼠、胎鼠生理指标。E17取材 ,用HPLC法检测给药组血中可卡因浓度及各组母鼠、胎鼠纹状体多巴胺 (dopamine ,DA)、5 羟色胺 (sero tonin ,5 HT)的浓度。结果　可卡因给药组 (COC)与盐水对照组 (SAL)相比 ,母体体重增长量及总摄食量均减少 ,纹状体多巴胺和 5 羟色胺含量增高 (COCn =16 ,SALn =11,P<0 0 1) ;胎鼠体重、脑重、纹状体重也存在明显差异 (SALn=76 ,COCn =92 ,P <0 0 1)。而可卡因给药组与饮食对照组 (SPF)相比 ,在母鼠摄食量相等、体重增长量无明显差异 (COCn =16 ,SPFn =12 ,P >0 0 1)的情况下 ,胎鼠的各项生理指标均下降 (COCn =92 ,SPFn =6 5 ,P <0 0 1) ,且脑纹状体多巴胺、5 羟色胺水平明显升高 ,分别为 (88± 12 )ng·g-1,(2 4 2± 18)ng·g-1。结论　宫内暴露可卡因可引起子代神经系统发育异常 ,这种发育异常?     

Effect of phenytoin on calcium disposition in pregnant and nonpregnant mice

The effect of phenytoin (DPH) on absorption and distribution of calcium in the male, female, and pregnant female mouse was evaluated. Pretreatment with phenytoin (80 mg/kg, ip × 5 days) significantly reduced the po absorption of ⁴⁵Ca in all three treatment groups. Distribution studies at 24 hr demonstrated that DPH pretreatment reduced femur bone concentration of IV administered ⁴⁵Ca to 40% of control value in all treatment groups. No significant effect of DPH was observed in the 24-hr soft tissue (liver, kidney, and brain) accumulations of ⁴⁵Ca. Fetal (Day 18) concentrations of radioactivity at 24 hr following ⁴⁵Ca administration were 25-fold greater than maternal soft tissue and approximated values observed in maternal bone, but no significant effect on fetal concentrations of ⁴⁵Ca was observed in phenytoin-pretreated mice. These results suggest that the fetal active uptake system of calcium differs significantly from intestinal or bone active transport systems and is probably not affected by chronic phenytoin therapy.     

Cocaine concentrations in fetal C57BL/6 mouse brain relative to maternal brain and plasma

Cocaine concentrations in maternal plasma and brain and fetal brain of mice were evaluated as a model for fetal brain exposure during maternal cocaine use. On days 12–18 of gestation, mice (C57BL/6; N = 5–7/group) received SC cocaine-HCl: 20 or 40 mg/kg. Maternal plasma and brain (accumbens and caudate nuclei removed), and fetal brain were collected at 0.5, 1, and 2 h following the last injection. Analysis was by GC-MS. Brain cocaine levels in the dams declined from 9.6 to 3.4 and 20.9 to 12.5 mg/g during the 0.5–1-h period after the low and high doses, respectively, and were 7.5–14.3 times greater than plasma levels. The corresponding fetal brain concentrations changed from 1.6 to 1.3 and 2.9 to 3.4 mg/g. By 2 h, brain cocaine concentrations in dams declined to approximately 10% of their 0.5-h values, with a slower drug decay occurring in fetal brain. Maternal plasma cocaine concentrations correlated with those of maternal brain (r = 0.94, p < 0.01) and fetal brain (r = 0.69, p < 0.01). The present results indicate that cocaine accumulates to a lesser extent in fetal brain than in maternal brain of C57BL/6 mice; however, the duration of exposure appears to be more sustained in the fetus, a phenomenon that may have toxicological implications for human in utero cocaine exposure.     

Placental transfer,excretion, and disposition of [14C]Zectran and [14C]Mesurol in maternal and fetal rat tissues

Pregnant Sprague-Dawley rats were injected ip on the 18th and 19th days of gestation with a tracer dose of [¹⁴C]Zectran (Z) or [¹⁴C]Mesurol (M). The excretion and distribution of total ¹⁴C were examined in fetal and maternal tissues. The distribution of Zectran and Mesurol after an ip dose was characterized by rapid maternal distribution and placental transfer. A distribution and elimination phase was seen for 30–60 min postinjection. After 1 hr [¹⁴C]Zectran in the whole fetus fell very slowly (K_e = 0.086 hr). At 15 min 1.7 and 3.5% of an administered dose of Zectran and Mesurol, respectively, was recovered from the pooled rat fetuses of a dam. After 8 hr, 0.8 and 1.1%, respectively, of the administered ¹⁴C was still present in the pooled fetuses. Fetal kidney and heart contained the most ¹⁴C after both Zectran and Mesurol administration. Liver was the maternal tissue with highest ¹⁴C content. More radioactive ¹⁴CO₂ derived from [¹⁴C]Zectran and [¹⁴C]Mesurol was exhaled by the nonpregnant rat (Z = 82.6%; M = 76.7%) than by the pregnant rat (Z = 62.2%; M = 66.9%). There was no significant difference in urinary excretion of ¹⁴C by pregnant or nonpregnant rats with either Zectran or Mesurol administration. Based on total ¹⁴C activity recovered in the urine, feces, and exhaled air after 8 hr, the pregnant animal retained 10.4–23% more ¹⁴C than the nonpregnant rat treated with either Zectran or Mesurol.     

Placental transfer of quazepam in mice

The disposition of 14C-quazepam following a single 5-mg/kg po dose was studied at the postembryonic period (day 12 of pregnancy) and near-term (day 18 of pregnancy). In both 12- and 18-day pregnant mice, radioactivity from the quazepam dose was widely distributed in the maternal tissues, with the highest levels in the liver and kidneys. At the time points analyzed (1, 5, and 24 hr post-dose), radioactivity levels in the fetus were consistently 44% of the maternal plasma levels in 12-day pregnant mice. In 18-day pregnant mice, fetal radioactivity levels at these time points were consistently equal to or slightly greater than maternal plasma levels. This indicates that radioactivity was taken up and eliminated from fetal tissues at rates that were reasonably similar to those in corresponding maternal tissues. No accumulation of radioactivity was observed in the fetus or in maternal tissues in either the 12-day or the 18-day pregnant mice. In 18-day pregnant mice, concentrations of quazepam and its metabolites were measured either by gas-liquid chromatography or thin layer radiochromatography. In the maternal plasma, concentrations of quazepam, its first-formed metabolite, 2-oxoquazepam, and 3-hydroxy-2-oxoquazepam were relatively low at all time points; levels of N-desalkyl-2-oxoquazepam and 3-hydroxy-N-desalkyl-2-oxoquazepam (HDOQ) were much higher. Fetal levels of unchanged drug and metabolites were generally less than or equal to maternal plasma levels, except for HDOQ levels, which were higher in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of acute and chronic cocaine administration in pregnant and nonpregnant rabbits.

The effects of cocaine administration on cardiovascular parameters were studied in anesthetized nonpregnant and pregnant rabbits with no prior exposure to cocaine and in pregnant rabbits repeatedly administered cocaine (4 mg/kg, bid, iv) for 15-20 days prior to the experiment. Rabbits were instrumented to determine the effects of cocaine on blood pressure, heart rate, and organ blood flows. Administration of the 1 and 2 mg/kg doses of cocaine increased blood pressure and decreased heart rate in both pregnant and nonpregnant rabbits. In contrast, the 4 mg/kg dose of cocaine caused reductions in both blood pressure and heart rate. Cocaine (1, 2, and 4 mg/kg, iv) also caused dose-dependent reductions in organ blood flows. Interestingly, cocaine did not affect uterine blood flow in the nonpregnant rabbits, whereas uterine and placental flows were markedly reduced in both groups of pregnant rabbits. Chronic treatment with cocaine caused a significant increase in the basal blood flow to the placenta and spleen, and a more precipitous decrease in blood flow in both organs in response to an acute injection of cocaine. The chronically treated rabbits also had a greater incidence of cardiac arrhythmias in response to an acute injection of cocaine (4 mg/kg, iv). Rabbits that received repeated administrations of cocaine experienced more prolonged reductions in blood flow than rabbits with no prior exposure to cocaine. These studies show that cocaine has marked effects on organ blood flows and that pregnancy and repeated prior administrations of cocaine can enhance these effects.     

Disposition of cefixime in the pregnant and lactating rat. Transfer to the fetus and nursing pup

The disposition of cefixime, a potent, third generation, orally active cephalosporin, was characterized in the pregnant and lactating rat. After a single iv dose of 17.8 mg/kg 14C-cefixime to day 18 pregnant rats, the half-life for elimination of radioactivity from both maternal serum and placentas was 6.9 hr. Elimination from fetal plasma and tissues was somewhat longer, 12.5 and 13.7 hr, respectively. However, comparison of areas under the curve indicated that exposure of the fetuses to cefixime was far less than that of placentas. Whole body autoradiography showed the greatest radioactivity in maternal liver, kidney, and intestines. In the lactating rat, steady state plasma concentrations of 14C-cefixime were achieved by continuous ip infusion of 2.54 mg/kg/day via Alza osmotic Mini-pumps from days 10 to 14 postpartum. Plasma concentrations of radioactivity in the dams were, on the average, 70 times greater than in their nursing pups throughout the study. After 102 hr of drug infusion, total radioactivity in the body of the pups, including the stomach and intestinal contents, was 1% of the 14C-cefixime estimated to be in the mother's body at steady state. Overall, these data indicate that exposure of the developing rat fetus and nursing pup to cefixime after maternal drug administration is quantitatively small.     

Placental transfer of pyridostigmine in the rat

1. Carbon-14 labelled pyridostigmine in single doses was given by intramuscular injection to pregnant rats, and maternal blood, foetal and placental homogenates were examined for total radioactive content, pyridostigmine and its metabolite, 3-hydroxy-N-methyl pyridinium.

2. The level of radioactivity in all tissues was highest at 15 min and fell to negligible amounts at 24 hr. The concentrations in placenta were similar to those in maternal blood, but there was some indication of retention of radioactive drug in the placenta. The concentrations in the foetus were substantially lower, but the subsequent slow decline in concentration suggests that cumulation of the drug could occur with repeated doses.

3. The percentage of metabolite in the foetus was considerably higher than in placenta and blood, and the possible reasons for this are discussed.

     

Pregnancy enhances cardiotoxicity of cocaine: role of progesterone.

Contraction dynamics of isolated papillary heart muscles from nonpregnant, pregnant, and progesterone-treated nonpregnant Long Evans rats were studied during exposure to cocaine. With increasing cocaine concentrations from 10(-16) to 10(-4) M, papillary muscles from nonpregnant rats demonstrated a biphasic pattern of positive, then negative, inotropy. Only negative inotropy with increasing cocaine concentrations was observed in papillary muscles from pregnant and progesterone-treated nonpregnant rats. Papillary muscles from pregnant and progesterone-treated nonpregnant rats became nonfunctional at cocaine concentrations 1-4 orders of magnitude lower than those for nonpregnant rats. These findings demonstrate that pregnancy and progesterone treatment alter cocaine effects upon cardiac papillary muscle function and response patterns and shift the cocaine dose-function curve to the left when compared to the nonpregnant group. We conclude that pregnancy increases the direct cardiotoxicity to cocaine, and progesterone may be responsible for this enhanced cocaine toxicity.     

The metabolism and distribution of 2,4,5-trichlorophenoxyacetic acid in female rats

[1-¹⁴C]-2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) was fed to pregnant and non-pregnant female rats at various dosages, and expired air, urine, feces, internal organs and tissues were analyzed for radioactivity. During the first 24 hr, 75 ± 7% of the radioactivity was excreted in the urine and 8.2 ± 4.6% in the feces. No ¹⁴C was found in the expired air. There was no significant difference in the rate of elimination between the pregnant and nonpregnant rats, or among the dosages used. Radioactivity was detected in all tissues, with the highest concentration being found in the kidney. The maximum concentration of radioactivity in all tissues was generally reached between 6 to 12 hr after po dosing and then started to decline rapidly. Radioactivity was also detected in the fetuses and in the milk. The average biological half-life of 2,4,5-T in the organs was 3.4 hr for the adult rats and 97 hr for the newborn.     

On the metabolism of ethyl-DL-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride (Tilidine-HCl). 2nd Communication: Studies with 14C-labelled substance on rats and dogs]

Absorption, distribution, metabolism and excretion of the potent analgesic ethyl-DL-trans-2-timethylamino-1-phenyl-chclohex-3-ene-trans-1-carboxylate-hydrochloride (tilidine-HCl, G? 1261 C, active ingredient of Vloron) were investigated in rats and dogs, using the radioactively labelled substance. Following oral administration, tilidine-HCl is rapidly and completely absorbed from the duodenum. During absorption, tilidine undergoes a marked first-pass effect. In plasma several metabolites are found, part of them occurring in higher concentrations than the unchanged substance. The metabolites are also formed rapidly after parenteral administration, unchanged tilidine being found in higher concentrations than any of the metabolites at all times measured. Following both routes of administration, the Met. I (nortilidine), also possessing a strong analgesic activity, reaches similar plasma levels. 14C distribution studies in rats showed a relatively high concentration of the radioactivity in the excretory organs, liver and kidneys. In brain, muscle tissue and blood much lower 14C concentrations are found. The concentrations measured in the foetal organs correspond to those in the muscle tissue of the mother animals and are, therefore, much lower than in most maternal organs. The radioactivity is eliminated from the foetal organs at the same rate as from the maternal organs. Tilidine is rapidly and completely eliminated with the excrements, nearly exclusively in the form of metabolic products. Rats eliminate 50% of the given radioactivity via the kidneys. The relatively high fecal elimination is based on the biliary metabolites. Following intraduodenal and intravenous administration to rats with an interrupted enterohepatic circulation, about 80% of the dose is eliminated with bile. The biliary metabolites are partly reabsorbed. In dogs, approx. 80% of the applied radioactivity is eliminated with urine.     

Disposition of the radioprotector ethiofos in the rhesus monkey. Influence of route of administration

Plasma concentrations of ethiofos [S-2-(3-aminopropylamino)ethyl phosphorothioic acid, WR-2721] were compared following iv, ip, intraduodenal, and portal administration to the rhesus monkey. Plasma samples were analyzed for ethiofos, free WR-1065, [2-(3-aminopropylamino)ethanethiol], and total material convertible to WR-1065 (total WR-1065). In separate experiments, total radioactivity in plasma was compared following iv, ip, and intraduodenal administration of [14C]ethiofos; excretion of the radiolabel was measured in urine and in feces. Intraduodenal administration of unlabeled ethiofos rarely gave measurable levels of unchanged drug in plasma. In contrast, intraduodenal administration of [14C]ethiofos produced an average AUC for total radioactivity that was 62% of that for a 10-min iv infusion of [14C]ethiofos. Urinary excretion of radioactivity following iv and intraduodenal administration of [14C]ethiofos was 78.9 +/- 14.0% and 43.8 +/- 12.4%, respectively, whereas 1.9 +/- 0.5% and 9.7 +/- 6.3% was excreted in feces. After an ip dose of either labeled or unlabeled ethiofos, absorption of the dose was prolonged, but AUC values for total radioactivity or ethiofos and total WR-1065 were similar to those observed after the corresponding 10-min iv experiments. For either iv or portal routes, increases in ethiofos AUC values were observed for the same total dose when the infusion rate was increased from 1.25 to 15 mg/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic profile and placental transfer of a single intravenous injection of [<Superscript>14</Superscript>C]chlorpyrifos in pregnant rats

The pharmacokinetics and placental transfer of a single intravenous dose of 5.0 mg/kg (10 micro Ci/kg) ring-labeled [(14)C]chlorpyrifos were investigated in pregnant Sprague-Dawley rats at 11-13 days of gestation. Three rats were killed at 5, 15 or 30 min, or 1, 2, 4, 8, 12, 18, 24, 36, 48, 72 or 96 h after dosing. Radioactivity and 3,5,6-trichloropyridinol (TCP) were detected in all tissues 5 min after dosing. Chlorpyrifos was only found in maternal plasma and liver. Peak maternal plasma concentration of radioactivity ( micro g chlorpyrifos equivalents/ml) was 157 at 5 min, compared with 1.9 for fetal plasma at 15 min. The maximum concentrations of radioactivity ( micro g chlorpyrifos equivalents/g), detected in most tissues within 12 h of dosing, were, in descending order: liver (30), brain (29), placenta (21), and fetus (2). All peaks occurred at 5 min except for fetus and fetal plasma, which were at 15 min. TCP was detected by HPLC as the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 12.4 micro g/ml, and for the following tissues was: liver 4.3 ng/g fresh tissue, fetus 4 ng/g, placenta 2.97 ng/g, brain 1.68 ng/g, and fetal plasma 0.52 ng/g. All TCP peaks occurred at 5 min except for fetus at 30 min and fetal plasma at 15 min. Parent chlorpyrifos was detected in maternal plasma and liver at maximum concentrations of 5.1 micro g/ml and 0.40 micro g/g, respectively, at 5 min. Chlorpyrifos was detectable in maternal plasma up to 36 h after dosing, and in liver up to 24 h after dosing. Pharmacokinetic analysis best described radioactivity, chlorpyrifos, and TCP as disappearing biexponentially from plasma and tissues. The terminal elimination half-lives of radioactivity, chlorpyrifos and TCP from maternal plasma were 16, 18, and 16 h, respectively. The results indicate that (1). chlorpyrifos undergoes a rapid metabolism to its major metabolites (TCP); (2). chlorpyrifos and its metabolites are distributed to all maternal and fetal tissues and plasma; and (3). the elimination of chlorpyrifos and TCP is slow, with redistribution from lipid stores a likely determinant of elimination rates.     

Metabolic disposition and irreversible binding of 1-phenylcyclohexene in rats

The metabolic disposition of l-[¹⁴C]phenylcyclohexene ([¹⁴C]PC) was examined in rats after ip or iv drug administration. Radioactivity, which was accumulated by various organs, peaked within 30 min after ip administration of [¹⁴C]PC (0.21 mg/kg). A significant amount of this radioactivity was not extractable by repeated methanol extractions, indicating irreversible binding of [¹⁴C]PC metabolite(s) to tissue proteins. Following iv administration of [¹⁴C]PC (0.42 mg/kg), [¹⁴C]PC concentrations in blood declined biphasically with time; the blood elimination half-life of [¹⁴C]PC is 77 min. About 83% of the dose given was excreted in urine and feces within 54 hr of administration. About 35% of the dose was excreted in the bile in 1 hr. At least four [¹⁴C]PC metabolites were detected in the urine or bile. The bulk of the urinary radioactivity was composed of metabolites since less than 6% of [¹⁴C]PC given was excreted unchanged in the urine.     

The distribution of [14C]caprolactam in male,female and pregnant mice

The distribution of [¹⁴C]caprolactam was studied by whole-body autoradiography in male, female and 14.5-day-pregnant mice. This technique does not allow translocation or removal of soluble compounds from the sites of localization. Pregnant mice were frozen 20 min and 1, 3, 9 and 24 hr after oral administration of the compound. The non-pregnant mouse was frozen 3 hr after oral dosing; two male mice were frozen 20 min and 9 hr after intravenous administration. Radioactivity was rapidly absorbed from the stomach and distributed throughout the entire animal, including the foetuses. There was efficient elimination by the kidney and liver. Material secreted by the liver into bile and intestinal contents appeared not to be reabsorbed via the enterohepatic circulation. The kinetics of distribution and elimination appeared to be the same in male, female and pregnant animals. The only sites of retention of radioactivity after 24 hr were the umbilical cords, amnion, yolk sac, maternal lens, maternal Harderian gland and maternal liver. The distribution into and removal from the foetuses was typical of molecules that diffuse freely across the placenta. There was no retention of radioactivity in any foetal tissue. With the possible exception of some residual activity in the nasal epithelium, no localization was seen that would suggest a site of toxic action of caprolactam.     

Placental transfer and fetal distribution of fluoxetine in the rat

Previously conducted reproduction and teratology studies in rats (unpublished observations) exposed to fluoxetine have revealed no compound-related adverse effects on fertility and no teratogenic effects. In order to confirm embryonic/fetal exposure to fluoxetine and/or metabolites, dissection and whole-body autoradiographic techniques were utilized to determine the placental transfer and fetal distribution in 12- and 18-day-pregnant Wistar rats 1, 4, 8, and 24 hr following a single oral 12.5 mg/kg dose of [14C]fluoxetine. On gestation Days 12 (organogenesis) and 18 (postorganogenesis), peak concentrations of radiocarbon occurred 4-8 hr after dose administration in the placenta, embryo/fetus, amniotic fluid, and maternal kidney, brain, and lung, and declined slightly at 24 hr postdose. Maternal lung contained the highest tissue concentration of radiocarbon at all time points. Placenta and maternal brain, kidney, and liver contained moderate levels of radioactivity, while embryonic/fetal tissue, amniotic fluid, and maternal plasma contained low levels of radioactivity. Mean fetal concentrations of radiocarbon at 4, 8, and 24 hr on gestation Day 18 were higher than mean embryonic concentrations on Day 12 of gestation. Analytical characterization of radioactivity indicated that combined fluoxetine and norfluoxetine concentrations accounted for 63-80% of the total radiocarbon concentrations in embryonic/fetal tissue. Results indicated that embryonic/fetal and maternal tissue levels of fluoxetine were greatest at early time points and declined with time, while norfluoxetine tissue levels were highest at the 24-hr time point. Whole-body autoradiographic techniques demonstrated that radioactivity associated with [14C]fluoxetine and/or its metabolites traversed the placenta and distributed throughout the 18-day fetus 4 hr following dose administration. Visual and quantitative evaluations of the autoradiograms indicated that the highest fetal concentrations of radiocarbon were associated with brain and thymus. Results from these studies indicate that fluoxetine and norfluoxetine traverse the placenta and distribute within the embryo/fetus during the periods of organogenesis and postorganogenesis and confirm embryonic/fetal exposure of parent and metabolite in previous negative rat teratology and reproductive studies.