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21.
Nishida K Kobayashi M Miyamoto H Yoshikawa N Fumoto S Sasaki H Nakamura J 《The Journal of pharmacy and pharmacology》2011,63(5):736-740
Objectives The importance of drug lipophilicity on absorption from the liver surface was examined in rats using paraben derivatives, antipyrine, Sudan III, and Sudan blue. Methods The log partition coefficient (PC) of n‐octanol/water ranged from ?1.39 to 4.62. The compounds were applied to the rat liver surface using a cylindrical diffusion cell (i.d. 9 mm). Key findings The rate of absorption at 15 min was calculated to be 13.9% for paraben, much lower than that for its derivatives methylparaben, propylparaben and butylparaben (~80%). The obtained first‐order absorption rate constant (ka) of paraben, methylparaben, propylparaben and antipyrine increased according to lipophilicity. Further lipophilicity resulted in a fall in ka, implying the importance of affinity for lipids and water in absorption from the liver surface. Thus, a compound with a log PC of around 2.5 is considered to have maximum absorbability from the rat liver surface. A good relationship (r2 = 0.97) was recognized between the log ka and log reciprocal value with the square root of molecular weight of the compounds with a log PC below 2.5. Conclusions The rate of absorption of a drug from the liver surface could be estimated from physicochemical properties such as lipophilicity and molecular weight. 相似文献
22.
E. A. Sotaniemi O. T. Hokkanen J. T. Ahokas R. O. Pelkonen J. Ahlqvist 《European journal of clinical pharmacology》1977,12(6):429-435
Summary The clinical picture and drug metabolism in 36 consecutive patients with alpha-methyldopa — induced hepatic injury were investigated. The diagnosis was based on case history and biochemical, histological and follow-up studies after withdrawal the drug. Alpha-methyldopa-induced liver damage was found to occur in two phases, acutely within months and chronically within years after beginning treatment. Differences were also found in clinical symptoms and the results of liver tests on the patients if they were divided on the basis of the time factor. Drug metabolism was impaired in patients with alpha-methyldopa-induced liver damage, as indicated by low cytochrome P-450 level in liver biopsies and prolonged antipyrine elimination rate from plasma. Disappearance of the symptoms and normalisation of the liver tests after drug withdrawal occurred faster in patients with an acute type of hepatotoxicity than in subjects with delayed onset of the symptoms. The occurrence of hepatotoxicity in four members of a family suggests a genetic disposition to alpha-methyldopa-induced hepatic injury. The occurrence of two phases of liver damage suggests that a possible mechanism for acute hepatotoxicity might be an allergic reaction to metabolic intermediates produced during breakdown of alpha-methyldopa in the liver. For cases of delayed onset the cause might be increasing damage to microsomal liver protein due to covalent binding during long-term exposure to the drug. 相似文献
23.
E. A. Sotaniemi J. Ahlqvist R. O. Pelkonen H. Pirttiaho P. V. Luoma 《European journal of clinical pharmacology》1977,11(4):295-303
Summary The drug metabolizing capacity of the liver was investigated in 27 consecutive alcoholics by comparison of in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) indices of drug metabolism with quantitative histological determinations of fat, trabeculae and non-fatty parenchyma in liver biopsies, and with biochemical liver function tests. The reduced amount of hepatic parenchyma in the biopsies was related to diminished drug metabolizing capacity, both in vivo and in vitro. The accumulation of fat alone did not significantly alter the kinetics of antipyrine, although it was associated with reduced cytochrome P-450 content. The replacement of parenchyma by fibrous tissue resulted in a decrease both in antipyrine clearance rate and cytochrome P-450 content. There was a logarithmic correlation between the kinetic parameters of antipyrine and cytochrome P-450 in the entire series, whereas a linear relationship was found in the alcoholic subjects in the various diagnostic groups. A non-linear relationship was also found between biochemical liver function tests and the in vivo and in vitro indices of drug metabolism. The results demonstrate that drug metabolizing capacity in alcoholics is related to ethanol-induced changes in the liver. quantitative evaluation of hepatic parenchymal changes, together with tests of the functional capacity of the liver, might be of significance value in predicting the ability of alcoholics to metabolize drugs. 相似文献
24.
H. I. Pirttiaho E. A. Sotaniemi J. Ahlqvist U. Pitkänen R. O. Pelkonen 《European journal of clinical pharmacology》1978,13(1):61-67
Summary The role of liver size in drug metabolism was investigated in 34 chronic alcoholics and 28 controls by comparing antipyrine half-life with biopsy content and total amount of hepatic cytochrome P-450 (P-450) and liver weight. Liver size was significantly greater in alcoholics than in controls. Total P-450 was increased and antipyrine metabolism was enhanced in alcoholics with normal histology of the liver. In subjects with alcoholic hepatitis or cirrhosis, the antipyrine half-life was prolonged and P-450 was decreased. Alcoholics with fatty liver had a reduced P-450 content, but the total amount of P-450 and the antipyrine half-life were normal. The results demonstrate in alcoholics that an enlarged liver of normal histological appearance is associated with enhanced drug metabolism. In subjects with fatty liver the drug metabolizing capacity per unit weight of liver is often impaired, but the increase in liver size leads to undisturbed total oxidizing capacity and normal in vivo metabolism. In alcoholic hepatitis drug metabolism is impaired in spite of hepatomegaly. In cirrhosis the enlargement of the liver appears to compensate for the decreased P-450 content resulting in only slightly decreased total P-450, and the severely impaired in vivo drug metabolism may be due to derangement of blood flow. 相似文献
25.
《Nutrition reviews》1981,39(6):232-234
The macronutrient composition of the diet has been shown to influence the oxidative biotransformation of two prototype drugs, antipyrine and theophylline, in both normal adults and asthmatic children. 相似文献
26.
The inactivation of endogenous steroids and foreign compounds by the liver hydroxylative pathway, can be modified by androgenic substances. The inhibitory or inductory activity, can be estimated by measuring the half-life of antipyrine. Androgens (testosterone propionate, 5α-dihydro-testosterone and mesterolone) reduce antipyrine metabolism in male rabbits. In females, androgens are not inhibitors, but one of them, 5α-dihydrotestosterone, shows an inductive effect on liver oxidative mechanisms. 相似文献
27.
P. V. Luoma E. A. Sotaniemi R. O. Pelkonen A. Arranto C. Ehnholm 《European journal of clinical pharmacology》1982,23(3):275-282
Summary The relationship between high-density lipoproteins (HDL) in plasma and hepatic structure and microsomal function has been investigated in 54 patients undergoing diagnostic liver biopsy. Plasma HDL cholesterol and major apoproteins were correlated with hepatic histology and microsomal enzyme activity assessed directly as liver cytochrome P-450 concentration and indirectly by plasma antipyrine clearance rate. HDL cholesterol, the concentrations of apoproteins A-I and A-II, the HDL cholesterol/total cholesterol ratio and cytochrome P-450 were low in subjects with moderate or severe hepatic fatty infiltration or cirrhosis when compared with the values for subjects with a normal liver. HDL cholesterol and apoprotein A-I and the HDL cholesterol/total cholesterol ratio were directly proportional to the amount of non-fatty parenchyma in the livers. Subjects with a normal liver undergoing treatment with enzyme-inducing drugs, such as phenytoin, phenobarbital and primidone, had higher HDL cholesterol, apoproteins A-I and A-II, HDL cholesterol/total cholesterol ratio, cytochrome P-450 and antipyrine clearance rate than subjects not receiving such therapy. Treatment with inducers appeared to have compensated for the effect of liver disease in lowering plasma HDL. In the entire population, and also in subjects not taking inducing drugs, when considered separately, plasma HDL cholesterol, apoproteins A-I and A-II and the HDL cholesterol/total cholesterol ratio were significantly correlated with cytochrome P-450 concentration. In subjects on enzyme inducers, HDL cholesterol and apoprotein A-I levels and the HDL cholesterol/total cholesterol ratio were proportional to the magnitude of the induction. Serum triglycerides were inversely proportional to the measures of liver microsomal enzyme activity. The lipoprotein pattern, high HDL cholesterol and apoproteins A-I and A-II, and high HDL cholesterol/total cholesterol ratio that accompany microsomal induction are characterized by a reduced risk of atherosclerotic vascular disease and a prolonged expectation of life. The plasma changes presumably reflect the effect of enzyme inducers, such as phenytoin and phenobarbital on hepatic lipids and proteins.The results have been presented at the annual meetings of the American Society for Clinical Pharmacology and Therapeutics, Kansas City, Missouri, 21–23 March 1979 [24] and the Scandinavian Society for Atherosclerosis Research, Turku, Finland, 31 August-1 September 1979 [23] 相似文献
28.
Shimoji K Esaki T Itoh Y Ravasi L Cook M Jehle J Jagoda EM Kiesewetter DO Schmidt K Sokoloff L Eckelman WC 《Synapse (New York, N.Y.)》2003,50(2):151-163
[(18)F][3-(3-(3-Fluoropropyl)thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine ([(18)F]FP-TZTP) is an M2 selective muscarinic agonist that may allow noninvasive studies of Alzheimer's disease with PET. 3-(3-(Propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (P-TZTP), a nonfluorinated analog of FP-TZTP, and unlabeled FP-TZTP inhibited [(18)F]FP-TZTP binding in vivo. Because muscarinic action of the loading dose of P-TZTP administered might have had pharmacological effects, the apparent inhibition might have resulted from reduced delivery rather than competition with receptor-binding. Therefore, we examined the effects of P-TZTP or FP-TZTP administration on cerebral blood flow (CBF) measured by the [(14)C]iodoantipyrine method and laser-Doppler flowmetry in rats. Statistically significant synchronous decreases in both CBF and mean arterial blood pressure (MABP) were observed within the first minute following administration. The decreases in both CBF and MABP were prevented by pretreatment with atropine methyl bromide (M-At), a peripheral muscarinic antagonist, and coadministration of M-At with either FP-TZTP or P-TZTP resulted in the same degree of inhibition of cerebral [(18)F]FP-TZTP-uptake 30 min after administration as observed without M-At. Also, with programmed infusions designed to produce constant arterial concentrations of [(18)F]FP-TZTP and FP-TZTP, which avoid changes in CBF, significant inhibition of [(18)F]FP-TZTP-binding by FP-TZTP was observed. These results indicate that inhibition of [(18)F]FP-TZTP-binding in the brain by P-TZTP or FP-TZTP in vivo occurs independently of their effects on CBF. The methods employed here may also be of interest to evaluate physiological effects of blocking agents utilized to validate other radiopharmaceuticals. 相似文献
29.
目的用高效液相色谱(HPLC)法测定复方柳安咖注射液中水杨酸钠、安替比林和咖啡因含量。方法采用Kromasil C18柱(250mm×4.6mm,5μm),以乙腈-0.1%磷酸二氢钾溶液(15:85)为流动相,流速为1.0mL/min,检测波长为272nm。结果水杨酸钠、安替比林和咖啡因进样量分别在0.7000~2、100Ixg(r=0.9999),0.2000--0.6000μg(r=0.9999)和0.1000—0.3000μg(r=0.9999)范围内与峰面积线性关系良好,平均回收率分别为99.1%,99.4%,99.7%,RSD分别为0.6%,0.5%,0.4%(n=9)。结论HPLC法可用于同时测定复方柳安咖注射液中水杨酸钠、安替比林和咖啡因的含量。 相似文献
30.
目的:研究钙离子拮抗剂地尔硫(DZ)对模型药安替比林(AP)在人体内代谢的选择性抑制作用。方法:6名健康男性志愿者,随机分成二组,分别po单剂量AP 800mg及加服DZ(30mg,tid),6d,取血并留尿48h,间隔2周后交叉给药。HPLC法测定血浆AP浓度和尿液中AP、3-羟甲基安替比林(3-OHMAP)、4-羟基安替比林(4-OHAP)、N-去甲基安替比林(NorAP)的浓度。结果:加服DZ后,APt1/2(Ke)从(13.79±3.17)h延长至(18.54±3.14)h(P<0.01),Cls从(40.42±7.62)ml·min-1减少至(28.64±5.84)ml·min-1(P<0.01),cmax和AUC明显增加(P<0.05)。4-OHAP尿清除率从(12.91±3.40)ml·min-1减少至(3.50±0.78)ml·min-1(P<0.01),3-OHMAP和NorAP的尿清除率没有明显变化。结论:DZ选择性地抑制了AP在人体肝脏中的4-羟基化代谢途径,提示DZ是一作用较强的、选择性的肝药酶抑制剂。 相似文献