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Biomedical subjects

J R Bailey

Publications and source records attributed to J R Bailey.

64 records · Page 4Linked to original sources
PubMed1982

Placental transfer and metabolism of 17 alpha-ethynylestradiol-17 beta and estradiol-17 beta in the rhesus monkey.

The synthetic estrogen component of many oral contraceptives, 17 alpha-ethynylestradiol-17 beta (EE2) and the naturally occurring estrogen, estradiol-17 beta (E2) were studied in four pregnant rhesus monkeys (71% term: 108-121 days gestational age). Under ketamine anesthesia, catheters were implanted in the maternal femoral artery and fetal interplacental artery. After simultaneous i.v. administration of [3H]EE2-[14C]E2 to the maternal animal, serial blood samples were drawn from both mother and fetus. The estrogens and metabolites were identified and quantified by the comigration of radioactivity with reference standards in several high-performance liquid chromatography systems and subsequent selective enzyme hydrolysis of the conjugates. Only estrone (E1), E1 sulfate, EE2 and EE2-3 sulfate were observed in the fetal circulation, whereas the major radiolabeled compounds in the maternal circulation consisted of the above plus E2, E1 glucuronide and EE2-3 glucuronide. In order to determine whether the placenta could convert E2 to its metabolite E1, the placentas of three term rhesus monkeys were perfused in situ via the umbilical artery with 120 ml (15 ml/min) of Hanks' balanced salt solution (pH 7.4) containing [3H]E2. High-performance liquid chromatographic analysis of umbilical vein samples revealed that 96% of the E2 was metabolized to E1. These studies indicate that the placenta can metabolize the potent naturally occurring estrogen E2 to the less potent E1. In contrast, the synthetic estrogen EE2 does not undergo this placental metabolic conversion and thus enters the fetal circulation as the parent compound.

Animals↗
PubMed1980

Transplacental pharmacokinetics and metabolism of diethylstilbestrol and 17 beta-estradiol in the pregnant rhesus monkey.

Experiments were performed to describe and compare the transplacental pharmacokinetics of the teratogen and transplacental carcinogen, diethylstilbestrol [4,4'-dihydroxy-alpha,alpha'-diethyl-trans, cis-stilbene (DES)], and the endogenous estrogen, 17 beta-estradiol (E2). Timed mated pregnant rhesus monkeys (119-137 days gestation) were anesthetized, and catheters were implanted in the maternal femoral artery and the interplacental fetal artery and vein using an extraamniotic technique. Single doses of either radiolabeled DES or E2 were administered via the maternal radial vein. Maternal plasma levels of labeled compound decreased rapidly after dose administration. Fetal plasma levels of radioactivity derived from either DES or E2 increased rapidly and then plateaued higher than maternal levels 1--2 h after dose administration. High pressure liquid chromatography of maternal and fetal plasma samples revealed both parent and conjugated metabolites of DES and E2. The principal metabolite of DES (DES monglucuronide) was radiolabeled and given to either the mother or the fetus iv. There was no significant cross-over of this metabolite in either direction. It is concluded that DES crosses the primate placenta in an unconjugated form and that, based on total radioactivity, placental transfer is similar to that of E2. The extensive fetoplacental metabolism of DES appears to be responsible for the greater half-life of this agent and its metabolites in the fetal circulation compared with the maternal circulation.

Animals↗
PubMedDate not supplied

Pharmacokinetics of cocaine in pregnant and nonpregnant rhesus monkeys.

To determine pharmacokinetic parameters for cocaine in rhesus monkey plasma, samples were taken over several hours after i.m. administration of cocaine plus a tritiated cocaine tracer. Cocaine and its metabolites, benzoylecgonine and norcocaine, were isolated via HPLC and quantitated using liquid scintillation spectrometry. Pregnant subjects were dosed with cocaine at 0.3 (n = 3) or 1.0 (n = 3) mg/kg, whereas nonpregnant female subjects were dosed with 1.0 mg/kg (n = 3). For the pregnant subjects, pharmacokinetic studies were conducted on about gestational day 125 and areas under the concentration versus time curve (AUCs, ng/mL x h) were 64 +/- 26 (+/- SEM) and 143 +/- 12; half-lives (t1/2s, h) were 1.9 +/- 0.6 and 1.1 +/- 0.1 after 0.3 and 1.0 mg/kg i.m., respectively. For nonpregnant subjects dosed acutely with 1.0 mg/kg, the AUC was 262 +/- 63 and the t1/2 was 1.4 +/- 0.3. There appear to be few differences in the pharmacokinetic parameters of cocaine and benzoylecgonine between pregnant and nonpregnant monkeys in this study.

Animals↗
PubMedDate not supplied

Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate.

MDMA (3,4-methylenedioxymethamphetamine) has been reported to produce serotonergic depletion in nonhuman primates at doses as low as 2.5 mg/kg (1-2 times the typical human dose). The current study evaluated the dose-response relationships of MDMA (1.25-20.0 mg/kg) using regional concentrations of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and home cage behavior as endpoints. Adult female rhesus monkeys (n = 16) were treated orally with 0, 1.25, 2.5, or 20.0 mg/kg MDMA twice daily for 4 consecutive days. Eighteen behaviors were measured in the home cage prior to, during, and after MDMA treatment. One month after the last dose, the animals were sacrificed and brains dissected into several regions for neurochemical analyses. 5-HT and 5-HIAA were analyzed via HPLC/EC. The lower doses of MDMA (1.25 and 2.5 mg/kg) did not significantly alter 5-HT or 5-HIAA concentrations in any brain region except hippocampus in which 5-HT concentrations were decreased after 2.5 mg/kg. MDMA at 20.0 mg/kg significantly decreased 5-HT and 5-HIAA concentrations in several cortical and midbrain structures. However, 5-HT and 5-HIAA concentrations in brain stem and hypothalamus were not significantly altered after any dose of MDMA. Combined with previous data from this laboratory, these results indicate that the decreased concentrations of 5-HT and 5-HIAA in selected brain regions show a selective dose-response relationship for MDMA-induced neurotoxicity as measured by serotonergic depletion in the nonhuman primate.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Metabolism of 14C-labeled doxylamine succinate (Bendectin) in the rhesus monkey (Macaca mulatta).

The time-course of the metabolic fate of [14C]doxylamine was determined after the p.o. administration of 13 mg/kg doxylamine succinate as Bendectin plus [14C]doxylamine succinate to the rhesus monkey. Urine and plasma samples were analyzed by reversed-phase high performance liquid chromatography (HPLC), chemical derivatization, and mass spectrometry. The cumulative 48-hr urinary metabolic profile contained 81% of the administered radiolabeled dose and consisted of at least six radiolabeled peaks. They were peak 1: unknown polar metabolites (8% of dose); peak 2: 2-[1-phenyl-1-(2-pyridinyl)ethoxy] acetic acid, 1-[1-phenyl-1(2-pyridinyl)ethoxy] methanol, and another minor metabolite(s) (31%); peak 3: doxylamine-N-oxide (1%); peak 4a: N,N-didesmethyldoxylamine (17%); peak 4b: doxylamine (4%); and peak 5: N-desmethyldoxylamine (20%). The plasma metabolic profile was the same as the urinary profile except for the absence of doxylamine-N-oxide. The maximum plasma concentrations and elapsed time to attain these concentrations were as follows. Peak 1: 540 ng/mL, 4 hr; peak 2: 1700 ng/mL, 1 hr; peak 4a: 430 ng/mL, 4 hr; peak 4b: 930 ng/mL, 2 hr; and peak 5: 790 ng/mL, 2 hr. These data suggest that in the monkey, doxylamine metabolism follows at least four pathways: a minor pathway to the N-oxide; a minor pathway to unknown polar metabolites; a major pathway to mono- and didesmethyldoxylamine via successive N-demethylation; and a major pathway to side-chain cleavage products (peak 2) via direct side-chain oxidation and/or deamination.

Animals↗
PubMedDate not supplied

Plasma pharmacokinetics and metabolism of 13-cis- and all-trans-retinoic acid in the cynomolgus monkey and the identification of 13-cis- and all-trans-retinoyl-beta-glucuronides. A comparison to one human case study with isotretinoin.

In order to compare the disposition and metabolism of 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (all-trans-RA) in the nonpregnant female cynomolgus monkey, the plasma concentrations of the parent compound, the oxidized metabolites 4-oxo-13-cis-retinoic acid and 4-oxo-all-trans-retinoic acid, and the conjugate metabolites 13-cis-retinoyl-beta-glucuronide (13-cis-RAG) and all trans-retinoyl-beta-glucuronide (all-trans-RAG), were determined on day 1 and day 10 after oral dosing of 2 and 10 mg 13-cis- and all-trans-RA/kg/day. Both 13-cis-RAG and all-trans-RAG have been identified as major plasma metabolites in these studies using thermospray/HPLC/mass-spectrometry of the intact conjugates. AUC comparisons from 0-24 hr after administration indicated that 13-cis-RA treatment resulted in primarily cis metabolites and all-trans-RA treatment resulted in primarily trans metabolites, although low levels of isomerization products were observed. Comparison of the two doses (2 and 10 mg/kg, po) revealed that the AUCs were proportional to the dose administered. Although qualitatively similar, elimination of 13-cis-RA in the monkey was more rapid than in the human, and approximately a 10-fold greater dose of 13-cis-RA was required in the monkey to produce the AUC values comparable to the human. The elimination of all-trans-RA in monkey was faster than that of 13-cis-RA and tended to increase with repeated dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Changes in estrogen metabolism after chronic oral contraceptive administration in the rhesus monkey.

The metabolism and elimination of estradiol (E2) and ethynylestradiol (EE2) were examined in adult female rhesus monkeys treated with two different combinational oral contraceptive agents at 10x the human equivalent dose. Ethynerone/mestranol (20:1), anagestone/mestranol (10:1), or vehicle was administered by gavage over a 10-year period on a cycling schedule of 21 days of dosing followed by 7 days without. At the end of the 28-day cycle, six monkeys in each group were anesthetized and administered a 14C-E2/3H-EE2 dose iv. Serial blood samples collected before and up to 6 hr after dosing were analyzed for total radioactivity and the percentage of parent compound and each metabolite was determined by HPLC. Radioimmunoassay of the baseline samples revealed that the plasma concentration of endogenous E2 was lower in the ethynerone/mestranol-treated group as compared to the vehicle control group. The total radioactivity derived from 14C-E2 was more rapidly eliminated from the plasma of the ethynerone/mestranol group than the control group. In addition, the percentages of HPLC-resolved E2 and EE2 were less in the treated group while the percentages of estrone, estrone glucuronide, and EE2 3-sulfate were enhanced as compared to the control group. The anagestone/mestranol group exhibited the same trends as the ethynerone/mestranol group but the data were not generally statistically different from the control group. These data indicate that chronically administered progestin/estrogen oral contraceptive agents reduce endogenous plasma E2 concentrations at least in part by enhancing the biotransformation of E2 to rapidly eliminated metabolites.

Animals↗
PubMedDate not supplied

Transplacental pharmacokinetics and maternal/fetal plasma concentrations of cocaine in pregnant macaques near term.

The transplacental pharmacokinetics of cocaine were studied in three pregnant rhesus monkeys (Macaca mulatta) at 150-154 days of pregnancy (term approximately 165 days). Animals were dosed intramuscularly with cocaine hydrochloride at 1 mg/kg, supplemented with a tritiated cocaine tracer. Plasma cocaine and its metabolite benzoylecgonine levels were determined after separation by HPLC and subsequent quantification by liquid scintillation spectrometry. Cocaine levels peaked in maternal blood within 10-20 min after dosing, and cocaine was detected in fetal blood within 5 min, reaching peak concentrations within 30-120 min. Mean maternal elimination half-lives (t1/2) for cocaine and benzoylecgonine were 1.2 +/- 0.5 hr and 12.4 +/- 6.6 hr (+/- SEM), respectively; fetal half-lives were 0.5 +/- 0.2 and 7.7 +/- 3.0 hr. Mean maternal residence times were 1.9 +/- 0.5 and 17.0 +/- 9.1 hr for cocaine and benzoylecgonine, respectively; fetal values were 2.1 +/- 0.2 and 11.6 +/- 3.5 hr. Total areas under the concentration versus time curves (AUCs) for cocaine and benzoylecgonine in maternal plasma were 360 +/- 38 and 585 +/- 260 (ng/ml) hr, respectively; fetal values were 104 +/- 29 and 262 +/- 61 (ng/ml) hr. Based on AUC comparisons for cocaine, fetal exposures are thus approximately one-third of maternal exposures, demonstrating that substantial exposure to cocaine does occur in utero.

Acid-Base Equilibrium↗