26 research outputs found

    Maternofetal transfer of phenytoin, p-hydroxy-phenytoin and p-hydroxy-phenytoin-glucuronide in the perfused human placenta

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    1. Transplacental transfer of the anti‐epileptic agent phenytoin (PHT), its phase I metabolite, p‐hydroxy‐phenytoin (p‐OH‐PHT), and its phase II conjugate p‐OH‐PHT‐glucuronide, was studied in term placental lobules perfused single pass in both maternal and fetal circuits. 2. Ratios of clearance of PHT, p‐OH‐PHT and p‐OH‐PHT‐glucuronide to clearance of antipyrine were 1.08 ± 0.03, 0.52 ± 0.02 and 0.12 ± 0.01 (mean and s.e.m.), respectively. 3. Transfer was positively correlated with lipophilicity as measured by the apparent partition coefficient determined between octanol and pH 7.4 buffer. Copyrigh

    “radiochemically pure [1-<sup>14</sup>C]valproic acid”—a mixture of labeled structural isomers

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    Ongoing studies of the disposition of valproic acid (VPA) and its glucuronide conjugate required the radiolabeled drug for greater sensitivity and tracing of oxidation metabolites. [1-14C]VPA hereinafter called LABEL (radiochemical purity >98% as determined by paper and thin layer chromatography) was purchased from Amersham International, U.K. Quantitative analysis of VPA and VPA-glucuronide in bile and urine samples from rats given VPA and tracer LABEL by our standard gas chromatographic assay showed gross discrepancies with the results obtained by liquid scintillation counting of the same extracts. Examination of the purity of LABEL was therefore undertaken. Equilibration of LABEL between various organic-aqueous solvent pairs was identical to that of authentic VPA. However, gas chromatographic-mass spectrometric analysis of the trimethylsilyl derivative of LABEL revealed it to be a mixture of labeled 2-methylheptanoic acid (—60%), 2-ethyl-hexanoic acid (-30%), and 2-propylpentanoic acid (i.e., VPA, 5-10%). The origin of the isomers of VPA in LABEL was logically traced to the synthetic procedure—coupling of the Grignard reagent of (an isomeric mixture of 2-, 3-, and 4-) chloroheptane(s) with [14C]carbon dioxide. This result highlights the inadequacy of the quality control procedures used and reinforces the necessity for caution in accepting the quoted purity of radiolabeled drugs

    Disposition of phenytoin and phenobarbitone in the isolated perfused human placenta

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    b 1. The disposition of the anti‐epileptic agents phenytoin (PHT) and pheno‐barbitone (PB) was investigated in lobules of term human placentae perfused using separate maternal and fetal circulations for 6 h periods. 2. No evidence for metabolism of PHT or PB to their p‐hydroxylated or other derivatives was found either in perfused lobules or by incubation with placental microsomes. 3. Both PHT and PB were readily transferred across the placenta after administration to either the maternal or fetal perfusates. 4. PHT, unlike PB, showed considerable accumulation in placental tissue. Copyrigh

    Impaired biliary elimination of ÎČ-glucuronidase-resistant 'glucuronides' of valproic acid after intravenous administration in the rat. Evidence for oxidative metabolism of the resistant isomers

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    A major metabolite of valproic acid (VPA) is its glucuronic acid conjugate (VPA-G). The disposition of VPA-G was compared with that of its intramolecularly rearranged, ÎČ-glucuronidase-resistant isomers (collectively called VPA-G-R) after iv bolus administration to pentobarbitone-anesthetized rats. VPA-G was eliminated from blood more rapidly than VPA-G-R. After administration of dose A (predominantly VPA-G) and dose B (predominantly VPA-G-R) to rats with catheterized bladders and bile ducts, total conjugated VPA in blood declined from 110ÎŒg of VPA/ml at 2 min to 1.1 ÎŒg/ml at 1 and 3 hr, respectively. A role for systemic hydrolysis of VPA-G was demonstrated by blood concentrations of free VPA which increased until 30 min. A minor role for systemic hydrolysis of VPA-G-R may be possible but cannot be proved from the current data. Urinary excretion (57 and 56% of doses A and B, respectively, in 3 hr) was greater than biliary excretion (32 and 10% of the doses, respectively, in 3 hr). The lower biliary elimination of VPA-G-R may be caused in part by impaired transport from blood to hepatocytes and/or hepatocytes to bile, but a role for phase I metabolism of the VPA moiety of VPA-G-R was demonstrated by recovery of 4.4% of dose B as 4-hydroxy-VPA. This latter mechanism was less (or not) applicable to VPA-G since only 0.4% of dose A was recovered as 4-hydroxy-VPA. Other VPA metabolites measured were quantitatively less important. These results were consistent in rats where either or both of the urinary and biliary elimination routes were surgically blocked

    Post–Cytochrome c Protection from Apoptosis Conferred by a MAPK Pathway in Xenopus Egg Extracts

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    In response to many different apoptotic stimuli, cytochrome c is released from the intermembrane space of the mitochondria into the cytoplasm, where it serves as a cofactor in the activation of procaspase 9. Inhibition of this process can occur either by preventing cytochrome c release or by blocking caspase activation or activity. Experiments involving in vitro reconstitution of apoptosis in cell-free extracts of Xenopus laevis eggs have suggested that extracts arrested in interphase are susceptible to an endogenous apoptotic program leading to caspase activation, whereas extracts arrested in meiotic metaphase are not. We report here that Mos/MEK/MAPK pathways active in M phase–arrested eggs are responsible for rendering them refractory to apoptosis. Interestingly, M phase–arrested extracts are competent to release cytochrome c, yet still do not activate caspases. Concomitantly, we have also demonstrated that recombinant Mos, MEK, and ERK are sufficient to block cytochrome c–dependent caspase activation in purified Xenopus cytosol, which lacks both transcription and translation. These data indicate that the MAP kinase pathway can target and inhibit post–cytochrome c release apoptotic events in the absence of new mRNA/protein synthesis and that this biochemical pathway is responsible for the apoptotic inhibition observed in meiotic X. laevis egg extracts
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