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THE EFFECT OF HYPOKINESIA ON LIPID-METABOLISM IN ADIPOSE-TISSUE

ACTA ASTRONAUTICA 1984年第10-1期11卷 735-738页

作者： MACHO, L KVETNANSKY, R FICKOVA, M TheInstituteofExperimentalEndocrinology SlovakAcademyofScienceBratislavaCzechoslovakia.

The increase of nonesterified fatty acid (NEFA) concentration in plasma was observed in rats subjected to hypokinesia for 1-60 days. In the period of recovery (7 and 21 days after 60 days immobilization) the content of NEFA returned to control values. The increase of fatty acid release from adipose tissue was observed in hypokinetic rats, however the stimulation of lipolysis by norepinephrine was lower in rats exposed to hypokinesis. The decrease of the binding capacity and a diminished number of beta-adrenergic receptors were found in animals after hypokinesia. The augmentation of the incorporation of glucose into lipids and the marked increase in the stimulation of lipogenesis by insulin were found in adipose tissue of rats subjected to long-term hypokinesia. These results showed an important effect of hypokinesia on lipid mobilization, on lipogenesis and on the processes of hormone regulation in adipose tissue.

关键词：脂细胞/代谢脂肪组织/细胞学脂肪组织/药物作用脂肪组织/代谢肾上腺素能β受体拮抗剂/代谢结合部位二氢烯丙洛尔/代谢肾上腺素/代谢脂肪酸类非酯化/血液脂肪酸类非酯化/代谢运动机能减退/代谢固位胰岛素/代谢脂解作用/生理学去甲肾上腺素/代谢去甲肾上腺素/药理学大鼠 Wistar 时间因素失重模拟动物男(雄)性大鼠

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Synthesis, stereoselective enzymatic hydrolysis, and skin permeation of diastereomeric propranolol ester prodrugs

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第5期88卷 544-550页

作者： Udata, C Tirucherai, G Mitra, AK Univ Missouri Div Pharmaceut Sci Sch Pharm Kansas City MO 64110 USA

Four diastereomeric propranolol ester prodrugs (1S2S, 1S2R, 1R2S, 1R2R) were synthesized by treating pure R- and S-propranolol hydrochloride with pure enantiomers R- and S-phenylbutyryl chloride. A HPLC technique using alpha-1 acid glycoprotein (chiral AGP) column was developed to study the racemization of propranolol enantiomers during synthesis and hydrolysis studies. A reversed phase HPLC method was also developed to simultaneously analyze propranolol and the ester prodrug. Hydrolysis of these esters was studied in different rat tissue homogenates, i.e., liver, intestine, plasma, skin, brain, and pure plasma cholinesterases, i.e., butyryl cholinesterase (EC 3.1.1.8) and acetyl cholinesterase (EC 3.1.1.7). In vitro percutaneous permeation studies across full thickness shaved rat skin were performed using standard side-by-side diffusion cells at 37 degrees C. The disappearance of the diastereomeric ester prodrugs in rat tissue homogenates followed apparent first-order kinetics and was stereoselective. The ratio of brain to plasma hydrolytic rate constants are 27.8, 5.58, 6.07, and 2.97 for 1S2S, 1R2R, 1R2S, and 1S2R esters, respectively. Hydrolysis of all four diastereomeric ester prodrugs was faster by acetyl cholinesterase than butyryl cholinesterase and is stereoselective. The permeability coefficients [K-p x 10(3) (cm h(-1))] are 1.40 +/- 0.30, 1.41 +/- 0.27, 42.20 +/- 1.24, 29.26 +/- 3.41, 16.27 +/- 3.12, 12.99 +/- 2.84 for (R)-propranolol, (S)-propranolol, 1S2S, 1R2S, 1S2R, and 1R2R ester prodrugs, respectively. The results indicate that the 1R2S diastereomeric ester prodrug of propranolol shows greatest stability in liver and intestinal tissues while it exhibits fairly rapid conversion in plasma. The results also suggest the configuration on the second chiral carbon atom to be the determinant in the rate of hydrolysis of all the diastereomeric prodrugs in all biological media examined. The K-p of all four prodrugs markedly increased compared to that of the p

关键词：肾上腺素能β受体拮抗剂/代谢氢离子浓度水解作用通透性药物前体/化学药物前体/代谢普萘洛尔/化学普萘洛尔/代谢大鼠 Sprague-Dawley 皮肤/代谢立体异构现象动物男(雄)性大鼠

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Inhibition of CYP2D6 by quinidine and its effects on the metabolism of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 41-51页

作者： Bramer, SL Suri, A Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: In vitro results are inconclusive as to whether cilostazol is metabolised by cytochrome P450 isoenzyme 2D6 (CYP2D6). The goals of this study were (1) to assure the dose of quinidine and timing relative to cilostazol used in this study were adequate to cause inhibition of CYP2D6, (2) to evaluate carryover effects of quinidine administration, and (3) to evaluate the effect of CYP2D6 deficiency and administration of quinidine (a CYP2D6 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, randomised sequence, 2-period, crossover pharmacokinetic trial. Water alone (treatment without quinidine) or two 200mg oral doses of quinidine sulfate with water were administered 25 hours and 1 hour prior to a single 100mg dose of cilostazol in period 1. Study participants were crossed over to opposite treatment in period 2. Metoprolol 25mg, used as a positive control, was administered 1 hour after quinidine sulfate with water or using water alone to assess the magnitude of CYP2D6 inhibition by quinidine. Study Participants: 22 healthy nonsmoking Caucasian (14 male and 8 female) volunteers participated in the study. Main Outcome Measures: Serial blood and urine samples were collected at predose and after cilostazol administration to characterise cilostazol and its metabolite pharmacokinetics. Additional plasma samples were taken to assess the pharmacokinetics of quinidine. Urine samples were collected to measure metoprolol and hydroxymetoprolol. Results: Administration of metoprolol with quinidine caused a significant (p < 0.001) decrease in the urinary 4-hydroxymetoprolol/metoprolol ratio compared with administration of metoprolol alone (42-fold decrease, 0.065 vs 2.707). Hence, quinidine effectively converted extensive metabolisers of CYP2D6 to poor metabolisers of CYP2D6. The 21-day washout period was adequate to have complete recovery from quinidine inhibition of CYP2D6. The analys

关键词：投药口服肾上腺素能β受体拮抗剂/代谢肾上腺素能β受体拮抗剂/尿方差分析曲线下面积交叉研究细胞色素P450CYP2D6/拮抗剂和抑制剂药物相互作用酶抑制剂/药代动力学酶抑制剂/药理学半衰期代谢清除率美托洛尔/代谢美托洛尔/尿奎尼丁/药代动力学奎尼丁/药理学四唑类/投药和剂量四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/代谢血管舒张药/药代动力学成年人女(雌)性人类男(雄)性中年人

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Coupling efficiencies of β₁- and β₂-adrenergic receptors expressed alone or together in transfected GH₃ pituitary cells

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期290卷 980-988页

作者： Guerrero, SW Minneman, KP Emory Univ Dept Pharmacol Sch Med Atlanta GA 30322 USA

The relationship between rat beta(1)- and beta(2)-adrenergic receptors (ARs) and cyclic AMP (cAMP) responses was examined by inducible expression of each subtype in transfected GH, pituitary cells. Increasing expression of beta(1)- or beta(2)-ARs in stably transfected subclones increased basal cAMP, increased the potency of isoproterenol in stimulating cAMP formation, but did not change the maximal response. A linear relationship was observed between log B-max and -log EC50 for isoproterenol, with no significant differences between beta(1)- and beta(2)-ARs. When both subtypes were coexpressed at different densities and ratios, pharmacological analysis showed that both selective and nonselective agonists exerted their effects at least partially through both subtypes. Either subtype alone activated a maximal response when the other subtype was blocked, indicating a complete redundancy in coupling. Agonists could activate responses through either subtype, with responses mediated primarily through the subtype where the agonist was most potent. The nonselective agonist isoproterenol had similar potencies for activating both subtypes;however, the density and ratio of subtypes affected the relative potencies of the selective agonists norepinephrine and zinterol. We conclude that beta(1)- and beta(2)-ARs have similar coupling efficiencies in GH(3) cells, these efficiencies are not altered by coexpression of another subtype, they couple redundantly to cAMP formation, and the relative densities of beta(1)- and beta(2)-ARs control the potencies of selective agonists.

关键词：肾上腺素能β激动剂/代谢肾上腺素能β激动剂/药理学肾上腺素能β受体拮抗剂/代谢肾上腺素能β受体拮抗剂/药理学结合竞争性细胞培养的环AMP/代谢咪唑类/代谢咪唑类/药理学碘放射性同位素异丙硫半乳糖苷/药代动力学异丙硫半乳糖苷/药理学异丙肾上腺素/药理学动力学吲哚洛尔/类似物和衍生物吲哚洛尔/代谢吲哚洛尔/药理学垂体前叶/细胞学垂体前叶/代谢垂体前叶/生理学丙醇胺类/代谢丙醇胺类/药理学受体肾上腺素能β1/生物合成受体肾上腺素能β1/遗传学受体肾上腺素能β1/代谢受体肾上腺素能β2/生物合成受体肾上腺素能β2/遗传学受体肾上腺素能β2/代谢转染动物大鼠

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The clinical pharmacology of beta adrenergic blocking drugs

Journal of the Royal College of Physicians of London

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Journal of the Royal College of Physicians of London 1976年第1期11卷 21-34页

作者： McDevitt, D.G. Shanks, R.G. Prichard, B.N.C. United Kingdom

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Biotransformations with Rhizopus arrhizus and Geotrichum candidum for the preparation of (S)-atenolol and (S)-propranolol

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BIOORGANIC & MEDICINAL CHEMISTRY 2000年第8期8卷 2067-2070页

作者： Damle, SV Patil, PN Salunkhe, MM Inst Sci Dept Chem Bombay 400032 Maharashtra India

(+/-)-Atenoiol/(+/-)-propranolol and their acetates were incubated with the fungus Rhizopus arrhizus and Geotrichum candidum separately for different time intervals to afford (S)-atenolol/(S)-propranolol in good optical yield. The time and pH for this biotransformation was optimised. The present biodegradations using Rhizopus arrhizus and Geotrichum candidum provides a simple and useful method to obtain (S)-atenolol and (S)-propranolol which are active enantiomers of the beta-adrenergic blockers. (C) 2000 Elsevier Science Ltd. All lights reserved.

关键词：肾上腺素能β受体拮抗剂/化学肾上腺素能β受体拮抗剂/代谢阿替洛尔/化学阿替洛尔/代谢生物降解环境生物转化地丝菌属/化学地丝菌属/代谢氢离子浓度分子构象分子结构普萘洛尔/化学普萘洛尔/代谢根霉菌属/化学根霉菌属/代谢立体异构现象时间因素

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