Biomedical subjects

W Slikker

Publications and source records attributed to W Slikker.

204 records · Page 12Linked to original sources

PubMedDate not supplied

Ethynyl cleavage of 17 alpha-ethynylestradiol in the rhesus monkey.

17 alpha-Ethynylestradiol (EE2)[20,21-14C] and [9,11-3H] were administered by intragastric intubation to three adult female rhesus monkeys. Quantification of the tritium isotope indicated that the peak plasma radioactivity (3.4-6.8% of dose) occurred between 30 and 60 min, whereas 36-39% of the administered tritium appeared in the urine in the first 96 hr. Fecal excretion was 9.17.0% during the same period. Fractionation and isolation of the urinary conjugates were accomplished by chromatography on Sephadex LH-20 followed by HPLC. Cochromatography of radioactive fractions with authentic steroid glucuronide standards gave presumptive evidence for the presence of ethynylestradiol and estrone glucuronides. Following hydrolysis, the tritium-labeled natural estrogens, estrone and estradiol-17 beta, were identified with reverse-isotope recrystallization, demonstrating that the de-ethynylation of EE2 had occurred.

Animals↗

PubMedDate not supplied

Cytochrome P-450-dependent oxidation of the 17 alpha-ethynyl group of synthetic steroids. D-homoannulation or enzyme inactivation.

Metabolism of the 17 alpha-ethynyl group of the synthetic estrogen, 17 alpha-ethynylestradiol, by hepatic microsomes from female rhesus monkeys was studied. Incubation of 17 alpha-ethynylestradiol, labeled with 14C in both ethynyl group carbons, resulted in the formation of D-14C-homoestrone (identified by high performance liquid chromatography and gas chromatography-mass spectrometry) and 14CO2. The D-homoestrone appears to be formed by a rearrangement in which one ethynyl group carbon is incorporated into the D ring of the steroid (D-homoannulation) and the second is subsequently removed as CO2. Cofactor, inhibition, and subcellular fractionation studies on the rate of 14CO2 formation showed that the ethynyl group is oxidized by cytochrome P-450. Hepatic microsomes isolated from rhesus monkeys treated with phenobarbital, but not 3-methylcholanthrene or pregnenelone-16 alpha-carbonitrile, resulted in increased rates of 14CO2 formation. Oxidation of the 17 alpha-ethynyl group is postulated to produce a high energy intermediate which is rearranged by D-homoannulation. However, as an alternative reaction, this unstable intermediate might covalently bind and inactivate the cytochrome P-450 enzymes catalyzing its formation. In support of this hypothesis, both cytochrome P-450 concentrations and the rate of catalysis of the D-homoannulation pathway by this enzyme were significantly decreased in hepatic microsomes from rhesus monkeys which had been administered mestranol and/or ethynerone (17 alpha-ethynylated steroids) at dosage levels mimicking human exposure to oral contraceptive agents.

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↗

PubMedDate not supplied

Pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo-, and all-trans-4-oxo retinoic acid after intravenous administration in the cynomolgus monkey.

The intravenous pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo, and all-trans-4-oxo retinoic acid (RA) were determined in nonpregnant female cynomolgus monkeys. All-trans- and 13-cis-RA were injected at two doses (0.25 or 0.0125 mg/kg) and all-trans-4-oxo RA and 13-cis-4-oxo RA at 0.25 mg/kg. Total body clearance, volume of distribution, and volume of distribution at steady state of all-trans-RA were dose-dependent with greater values at the lower dose. Elimination half-life was longer for the cis-compounds and not dose-dependent (N = 1 for 13-cis-4-oxo RA, N = 3 for other compounds, harmonic mean +/- pseudostandard deviation, min): 13-cis-4-oxo RA (837) > or = 13-cis-RA (301 +/- 204) > all-trans-RA (38 +/- 3) > all-trans-4-oxo RA (11 +/- 2). Secondary plasma peaks were noted only after administration of 13-cis-4-oxo RA. The low area under the time concentration curves for observable metabolites after intravenous injection of the oxidated compounds suggests further metabolism plays a minimal role in the elimination of these compounds from the monkey. Plasma-time concentration curves were fitted to multicompartmental models and suggested < 30% of each compound was available in the central compartment for elimination in the postdistribution phase. A comparison of the kinetics of the isomers indicated oxidation of all-trans-RA to all-trans-4-oxo RA increased mean total body clearance values 4-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Food and Drug Administration Proposed Guidelines for Neurotoxicological Testing of Food Chemicals.

The fact that some chemicals may adversely affect the nervous system is certainly not a new concept in regulatory toxicology. In 1982, the FDA issued testing guidelines for the safety evaluation of proposed direct food and color additives which included the assessment of nervous system toxicity as part of the general toxicological profile. However, these guidelines provide only broad and nonspecific recommendations as to how this assessment may best be carried out. The information derived from toxicity screening studies conducted according to these guidelines enable little more than the detection of clearly evident adult nervous system toxicity associated with general neuropathology and overt neurological dysfunction. Little consistent or systematically documented information is typically developed about other equally important types of neurotoxic effects including, for example, behavioral dysfunction and developmental neurotoxicity. Concerns about these more subtle types of neurotoxic effects have become a prominent public health issue and have resulted in demands for an increasing level of assurance that efforts are being made to minimize even further the risks of neurotoxicity from human exposure to chemical substances. In an effort to address these concerns, the FDA is including specific attention to neurotoxicity in a proposed revision of its toxicity testing guidelines for food additives. These proposed guidelines focus on a more careful evaluation of structural and functional measures of neurotoxicity as a routine component of safety assessment. This focus will enable the development of the type of information needed for a more effective assessment of the full spectrum of neurotoxic hazards. The revised guidelines for neurotoxicity testing will be discussed in terms of the FDA's overall approach to safety assessment.

Food↗