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Effect of renal impairment on the pharmacokinetics of cilostazol and its metabolites

CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 33-40页

作者： Mallikaarjun, S Forbes, WP Bramer, SL Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: The pharmacokinetics of cilostazol were studied in patients with mild, moderate and severe renal impairment and in healthy volunteers after administration of 50mg single and multiple doses of cilostazol. Design: This was an open-label, single and multiple dose study administering 50mg cilostazol every 12 hours to healthy volunteers and patients with varying degrees of renal impairment. Participants: 6 normal volunteers [creatinine clearance (CLCR) greater than or equal to 90 ml/min];6 patients with mild (CLCR 50 to 89 ml/min), 5 with moderate (CLCR 26 to 49 ml/min) and 6 with severe (CLCR 5 to 25 ml/min) renal impairment. Outcome Measures: Noncompartmental pharmacokinetic parameters were determined for each study participant. Results: At steady state, in the severe renal disease group, cilostazol and OPC-13015 peak concentrations (C-max) were 24 and 41% lower and the areas under the concentration-time curve over the dosage interval (AUC(tau)) 39 and 47% lower than in the healthy volunteers. C-max and AUC(tau) of OPC-13213 were significantly higher, 173 and 209%, respectively, than those in the healthy volunteers. The accumulation ratios were not significantly different between the various renal function groups for cilostazol and its metabolites. The estimated pharmacological activity of cilostazol and its metabolites was similar between the normal volunteers and those with severe renal impairment. Conclusions: A dosage reduction in renally impaired patients is not supported by the pharmacokinetics of cilostazol and its metabolites in this patient group.

关键词：投药口服方差分析曲线下面积色谱法高压液相肌酸酐/代谢用药计划表半衰期代谢清除率参考值肾功能不全/分类肾功能不全/代谢疾病严重程度指数四唑类/投药和剂量四唑类/血液四唑类/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/血液血管舒张药/代谢血管舒张药/药代动力学女(雌)性人类男(雄)性中年人

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Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 69-77页

作者： Bramer, SL Brisson, J Corey, AE Mallikaarjun, S Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80mg on days 1, 7 and 9, as well as oral cilostazol 100mg twice daily on days 2 to 8, followed by a single oral 150mg cilostazol dose on day 9. Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. Results: The maximum observed plasma concentration (C-max) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(t)) for lovastatin coadministered with 100mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUC(t) ratios for lovastatin given with 150mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150mg of cilostazol. Maximum steady-state plasma drug concentration (C(ss)max) and AUC during a dosage interval (AUC(tau)) for cilostazol 100mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilos

关键词：方差分析抗胆固醇血症药/血液抗胆固醇血症药/代谢抗胆固醇血症药/药代动力学曲线下面积色谱法高压液相剂量效应关系药物用药计划表药物相互作用半衰期肠吸收/药物作用洛伐他汀/血液洛伐他汀/代谢洛伐他汀/药代动力学参考值四唑类/投药和剂量四唑类/血液四唑类/药代动力学四唑类/药理学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/药代动力学血管舒张药/药理学成年人女(雌)性人类男(雄)性中年人

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Effect of omeprazole on the metabolism of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 53-59页

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

Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40mg every day) was administered on days 7 to 18. Study Participants: 20 healthy nonsmoking male and female volunteers. Main Outcome Measures: Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites. Results: Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (C-max) and area under the plasma concentration-time curve at time t (AUC(t)) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 C-max and AUC(t) increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUC(t) decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole. Conclusions: Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.

关键词：投药口服曲线下面积血蛋白质类/代谢色谱法高压液相交叉研究药物相互作用酶抑制剂/药理学半衰期奥美拉唑/药理学四唑类/投药和剂量四唑类/血液四唑类/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/血液血管舒张药/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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Relative bioavailability and effects of a high fat meal on single dose cilostazol pharmacokinetics

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 13-23页

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

Objectives: The objectives of this research were to (1) assess the relative bioavailability following administration of a 100mg cilostazol suspension versus 100mg tablet;(2) assess dosage form equivalency (2 x 50mg compared with 1 x 100mg);(3) compare the relative bioavailability following a single 50mg dose of cilostazol administered as an ethanolic solution versus a 50mg tablet;and (4) determine the effects of high fat diet on the pharmacokinetics of cilostazol following a single dose of 100mg cilostazol in the fed or fasted state. Results were compiled from 3 separate studies to address these objectives. Design: All studies involved healthy adult males receiving single oral doses of cilostazol in the fed or fasted state. The fed state consisted of administering cilostazol after ingestion of a high fat meal. One study compared the relative bioavailability of 100mg suspension and 2 x 50mg tablet versus 100mg tablet in a randomised crossover design. The study involving administration of a 50mg cilostazol ethanolic solution was a single treatment study. The effects of food on the pharmacokinetics of cilostazol after administration of 100mg cilostazol in the fed or fasted state as well as the pharmacokinetic profile following administration of a single 50mg oral dose of cilostazol were assessed in a randomised crossover design. Study Participants: All participants were healthy nonsmoking males aged between 19 and 48 years whose bodyweight was within 15% of ideal bodyweight. Main Outcome Measures: Noncompartmental pharmacokinetic parameters: were determined for each study participant. Results: The area under the plasma concentration-time curve (AUC) parameters were within the 80 to 125% criterion for bioequivalence for the cilostazol and its primary metabolite, OPC-13015. The maximum observed plasma concentrations (C-max) for these formulations were not equivalent and indicated that the absorption of cilostazol from a suspension is more rapid than from a tablet. The ap

关键词：投药口服曲线下面积生物利用度交叉研究膳食脂肪类/药理学禁食/代谢悬液片剂四唑类/投药和剂量四唑类/血液四唑类/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/血液血管舒张药/代谢血管舒张药/药代动力学成年人人类男(雄)性中年人

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Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver cirrhosis

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AMERICAN JOURNAL OF GASTROENTEROLOGY 1999年第2期94卷 502-507页

作者： Li, CP Lee, FY Hwang, SJ Chang, FY Lin, HC Lu, RH Hou, MC Chu, CJ Chan, CC Luo, JC Lee, SD Vet Gen Hosp Dept Med Div Gastroenterol Taipei 11217 Taiwan Natl Yang Ming Univ Sch Med Taipei 112 Taiwan

Objective: Cutaneous spider angioma is a common sign observed in patients with liver cirrhosis, but its pathogenesis is still unclear. Increased plasma levels of estrogen, vascular dilation, and neovascularization are possible etiologies. This study was designed to investigate the relationship of spider angiomas in patients with nonalcoholic liver cirrhosis to the plasma levels of sex hormones and various vasodilators and hemodynamic parameters. Methods: A total of 60 patients with nonalcoholic liver cirrhosis and 20 healthy subjects were included in this study. The number, size, and location of the spider angiomas were recorded. Plasma levels of estradiol, testosterone, substance P, calcitonin gene-related peptide, and nitrate/nitrite and forearm hemodynamics were measured. Results: Cirrhotic patients showed higher plasma estradiol/testosterone ratios (28.3 +/- 47.2 x 10(-3), median 10.5 x 10(-3) vs 8.2 +/- 8.3 x 10(-3), median 5.7 x 10(-3), p = 0.003) and levels of nitrate/nitrite (29.9 +/- 17.5, median 23.8 vs 21.4 +/- 10.0, median 20.6 mu mol/L, p = 0.01) and substance P (47.5 +/- 62.5, median 29.2 vs 15.2 +/- 7.7, median 12.3 pg/ml, p < 0.001) than healthy controls. Sixteen (27%) of the 60 cirrhotic patients had spider angiomas. Cirrhotic patients with spider angiomas disclosed higher plasma levels of substance P (84.7 +/- 105.3, median 53.1 vs 34.5 +/- 30.7, median 25.8 pg/ml, p = 0.006) and serum levels of bilirubin (3.9 +/- 3.8, median 1.9 vs 1.9 +/- 1.9, median 1.2 mg/dl, p = 0.02) than those without. Stepwise logistic regression showed substance P was the only significant and independent predictor associated with the presence of spider angiomas in cirrhotic patients (odds ratio 3.0, 95% confidence interval = 1.4-6.6, p = 0.01). Conclusion: Plasma levels of substance P are elevated in patients with nonalcoholic cirrhosis and may play an important role in the pathogenesis of spider angiomas. (Am J Gastroenterol 1999;94:502-507. (C) 1999 by Am. Coll. of Gastr

关键词：病例对照研究雌二醇/血液前臂/血液供给肝硬化/血液肝硬化/并发症肝硬化/病理生理学 Logistic模型局部血流/生理学 P物质/血液 P物质/生理学毛细血管扩张/病因学睾酮/血液血管舒张药/血液老年人女(雌)性人类男(雄)性

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Nociceptin/orphanin FQ metabolism and bioactive metabolites

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PEPTIDES 2000年第7期21卷 919-922页

作者： Terenius, L Sandin, J Sakurada, T Karolinska Inst Karolinska Hosp Dept Clin Neurosci Expt Alcohol & Drug Addict S-17176 Stockholm Sweden Daiichi Coll Pharmaceut Sci Dept Biochem Minami Ku Fukuoka 8158511 Japan

Thr endogenous ligand for the orphan NOR receptor (earlier named ORL1) was recently discovered. This ligand, nociceptin/orphanin FQ is involved in a number of pharmacological actions in the CNS, including modulation of pain and cognition. However, its specific physiological role remains to be determined. Two major pathways of metabolism have been identified;the action of aminopeptidase(s) that prominently occurs in plasma, and endopeptidase activity that successively generates the N-terminal 1-13 and 1-9 fragments. Both pathways result in fragments that are inactive at the NOR receptor. However, short N-terminal fragments appear to be active in blocking the release of substance P from primary afferent C-fiber terminals in the dorsal spinal cord. The same endopeptidase(s) may also be involved in the fragmentation of dynorphin A since the inhibitor profile is similar. Enzyme activity is upregulated by morphine using either peptide as substrate that may lead to pharmacological interactions. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：氨基酸序列氨肽酶类/血液脑/代谢细胞系细胞培养的强啡肽类/代谢配体分子序列数据阿片样肽类/血液阿片样肽类/化学阿片样肽类/代谢肽类/代谢蛋白质前体/代谢受体阿片样/代谢脊髓/代谢肿瘤细胞培养的血管舒张药/血液血管舒张药/化学血管舒张药/代谢动物人类小鼠大鼠

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Plasma adrenomedullin levels in the coronary circulation in vasospastic angina pectoris

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AMERICAN JOURNAL OF CARDIOLOGY 2000年第5期85卷 656-+页

作者： Kamiya, H Okumura, K Sone, T Tsuboi, H Kondo, J Mukawa, H Matsui, H Toki, Y Ito, T Hayakawa, T Nagoya Univ Sch Med Showa Ku Nagoya Aichi 4668550 Japan Ogaki Municipal Hosp Dept Cardiol Ogaki Japan

This study evaluated the role of adrenomedullin in patients with vasospastic nagina pectoris. Adrenomedullin may be involved in regulating a basal tone of the coronary artery in these patients.

关键词：乙酰胆碱/诊断应用肾上腺髓质素心绞痛变异型/血液心绞痛变异型/病因学降钙素基因相关肽/血液病例对照研究冠状动脉循环肽类/血液肽类/生理学试点项目血管舒张药/血液血管舒张药/诊断应用老年人女(雌)性人类男(雄)性

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Determination of azide in blood and urine by gas chromatography-mass spectrometry

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JOURNAL OF ANALYTICAL TOXICOLOGY 2000年第6期24卷 429-432页

作者： Kage, S Kudo, K Ikeda, N Kyushu Univ Grad Sch Med Sci Dept Forens Pathol & Sci Higashi Ku Fukuoka 8128582 Japan Fukuoka Prefectural Police Headquarters Forens Sci Lab Hakata Ku Fukuoka 8128576 Japan

A sensitive and simple method for determining azide in blood and urine using an extractive alkylation technique was devised. This inorganic anion was alkylated with pentafluorobenzyl bromide using tetradecyldimethylbenzylammonium chloride as the phase-transfer catalyst. 1,3,5-Tribromobenzene was used as an internal standard. The obtained derivative was analyzed by gas chromatography–mass spectrometry using the negative ion chemical ionization mode with isobutane as the reagent gas. The calibration curves for azide were linear over the concentration range from 1 to 200 nmol/mL in blood and urine, and the lower limit of detection was 0.5 nmol/mL for blood and urine. The accuracy and precision of the method were evaluated, and the coefficients of variation were found to be lower than 10%.

关键词：法医学/方法气相色谱-质谱法/方法结果可重复性敏感性与特异性叠氮化钠/血液叠氮化钠/尿血管舒张药/血液血管舒张药/尿人类

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Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 1-11页

作者： Bramer, SL Forbes, WP Mallikaarjun, S Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: To study the pharmacokinetics of cilostazol following single oral administration of 50 to 200mg in healthy young males, and after repeated oral administration of 100mg every 12 hours to patients with peripheral arterial disease (PAD). Design: The healthy male single dose study was a single-centre, randomised sequence, open-label, incomplete block, 3-period, 4-treatment, crossover design. The patient study was a single-centre, multiple dose, open-label study. Study Participants: 20 healthy nonsmoking male volunteers were enrolled and successfully completed the single dose study. 26 patients (21 males, 5 females) with intermittent claudication resulting from PAD were enrolled and completed the single/multiple dose study. Main Outcome Measures: Noncompartmental pharmacokinetic parameters, the area under the plasma concentration-time curve from zero to the time of last measurable plasma concentration, and maximum plasma concentration. Results: Peak plasma concentrations of cilostazol occurred about 3 hours after drug administration and then declined biexponentially with concentrations detectable (>20 mu g/L) in the plasma for at least 36 hours postdose. The apparent elimination half-life of cilostazol (approximately 11 hours) was similar after a single dose or after multiple doses, with steady state being reached within 4 days. Cilostazol accumulated 1.7-fold following multiple dose administration. The apparent volume of distribution (V-2/F;2.76 L/kg) suggested extensive distribution of cilostazol in the tissues. The oral clearance of cilostazol (CL/F;0.18 L/h/kg) was much lower than liver blood flow, indicating a low extraction ratio drug, and hence low probability of a significant first-pass effect. None of the administered doses were recovered in the urine as unchanged cilostazol, suggesting that metabolism, rather than urinary excretion, is the major elimination route. Following single oral doses of 50 to 200mg, the plasma concentrations of cilostazol and

关键词：投药口服方差分析曲线下面积交叉研究用药计划表间歇性跛行/药物疗法间歇性跛行/病因学代谢清除率外周血管疾病/并发症外周血管疾病/药物疗法四唑类/投药和剂量四唑类/血液四唑类/药代动力学四唑类/治疗应用组织分布血管舒张药/投药和剂量血管舒张药/血液血管舒张药/药代动力学血管舒张药/治疗应用女(雌)性人类男(雄)性

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