Lack of inhibition of clomethiazole metabolism by cimetidine: model experiments in the dog

The disposition of clomethiazole was studied in six dogs subjected to pretreatment with cimetidine or saline according to a cross-over design. Pretreated dogs received approximately 20 mg/kg of cimetidine p.o. for 4 days and 30 mg/kg i.v. immediately before an intraduodenal infusion of clomethiazole (117 mumol/kg clomethiazole base within 90 min). Compared to controls, cimetidine had no effect on peak plasma concentrations and on areas under the plasma concentration time curves of clomethiazole or of its metabolite 5-acetyl-4-methylthiazole (P greater than 0.05). Identical pretreatment of the same dogs resulted in a 50% inhibition of aminopyrine demethylation (P less than 0.001) as revealed by the aminopyrine breath test. Clomethiazole may be metabolized in the dog through metabolic routes which cannot be inhibited by cimetidine.     

Impairment of drug metabolism in patients with liver cancer

Abstract. Drug metabolizing capacity was investigated in sixteen patients with cancer in the liver by comparing in vivo (antipyrine disappearance rate from plasma) and in vitro (cytochrome P-450, benzpyrene hydroxylase, and 7-ethoxycoumarin O-deethylase activities in liver biopsies) indices of drug metabolism with the condition of tumour-free liver parenchyma and with biochemical liver function tests. Drug metabolism was impaired as antipyrine hydroxylation was significantly lower than in matched controls. Impairment of antipyrine metabolism was related to the pathological changes in the liver; patients with metastatic liver cancer or with tumour and cirrhosis metabolized antipyrine at a reduced rate, whereas those with a hepatoma occupying from 20 to 80% of the liver volume had normal antipyrine metabolism. Liver enzyme activities were related to the site of the biopsy; values were low in and around the tumour tissue and high in normal parenchyma. The antipyrine half-life was related to serum albumin concentration but not to other liver function tests. The results demonstrate that in liver cancer patients the drug-hydroxylating capacity is dependent on the ability of the tumour-free parenchyma to metabolize drugs. Hence quantitative evaluation of liver changes together with tests measuring liver synthetic capacity might be of significance when predicting drug metabolism in patients with hepatic malignancy.     

Inhibition of hepatic demethylation of aminopyrine by oral contraceptive steroids in humans

The effect of oral contraceptive steroids (OCS) on the rate of hepatic demethylation of 14C-dimethylaminoantipyrine (DAP) was studied directly in healthy young volunteers using a newly developed noninvasive breath analysis technique. After oral administration of a trace dose of DAP the specific activity of 14CO2 in breath was determined during 6 h and expressed as half life. The half life of eighteen female and twelve male control subjects was 2.4 +/- 1.2 h (2 SD) and 2.2 +/- 0.6 h (2 SD), respectively. In seven women starting OCS a progressive prolongation of DAP half life during a single menstrual period was observed. In seventeen women who had taken OCS in 21 day cycles, for more than 3 months, the half life was significantly (P less than 0.001) prolonged (4.4 +/- 2.1 h) when measured after 21 consecutive days of OCS intake. On average, stopping OCS for 7 days or giving phenobarbital in addition to OCS shortened DAP half life significantly (from 4.4 +/- 2.1 h to 3.2 +/- 1.1 h, n = 17, P less than 0.005; and from 4.6 +/- 2.0 h to 3.2 +/- 1.0 h, n = 12, P less than 0.01, respectively). Eight of twelve women on OCS responded to OCS intake and to OCS cessation and phenobarbital, whereas four women did not respond to any of these measures. These data suggest that inhibition of hepatic demethylation of DAP by OCS is time dependent and reversible. The extent of inhibition appears to be an individual characteristic of a given person.     

Bufuralol metabolism in human liver: a sensitive probe for the debrisoquine-type polymorphism of drug oxidation

The genetically controlled polymorphism causing decreased metabolism of debrisoquine is closely related to that of the metabolism of bufuralol and numerous other drugs and has important clinical consequences. A sensitive in vitro assay was developed which quantifies the production of 1'-hydroxy-bufuralol (carbinol) from bufuralol in human liver microsomes. Initial formation rates of carbinol suggested Michaelis-Menten kinetics with an apparent KM of 61 and 171 mumol l-1 and Vmax of 3.2 and 5.8 nmol mg-1 microsomal protein h-1 in two human liver samples. The Vmax in microsomes of thirty-two liver samples was 4.2 +/- 1.0 (SD) nmol carbinol mg-1 protein h-1. Metabolism of debrisoquine in vivo, as expressed by the 'metabolic ratio' of debrisoquine over 4-OH debrisoquine correlated (r = -0.65, P less than 0.01; n = 18) with carbinol production rate in microsomes in vitro. Microsomes of one individual identified as poor metabolizer of debrisoquine in vivo showed reduction of carbinol formation to 1.97 nmol mg-1 h-1. Mixing his microsomes with those of an extensive metabolizer resulted in additive formation of carbinol excluding mediation of the defect by a soluble inhibitor. These data support the concept of a primary defect in microsomal oxidation of bufuralol. The described assay offers a sensitive tool to investigate the molecular mechanism of the 'debrisoquine polymorphism'.     

Clearance of antipyrine-dependence of quantitative liver function

Abstract. The purpose of the present study was to assess the influence of liver disease on the hepatic drug-metabolizing enzyme systems. The clearance of antipyrine was found to be significantly decreased in 13 patients with liver disease compared with 9 control patients (18.5 and 58.6 ml/min. respectively). Among the patients with liver disease, those with a severely reduced capacity for work had significantly lower clearance of antipyrine than non incapacitated patients (12.5 and 25.4 ml/min. respectively). The clearance of antipyrine was significantly correlated with the galactose elimination capacity, the serum albumin and the prothrombin values. The results indicate that the drug-metabolizing capacity of the liver changes in parallel with the other metabolic functions, and the use of the clearance of antipyrine as a quantitative test of liver function is suggested.     

Role of gastrointestinal tract and liver in acetate metabolism in rat and man

Net acetate uptake/release by various tissues was studied in vivo in fed, starved and Paromomycin-treated rats and in patients with cirrhosis of the liver. In humans the portal vein, hepatic vein and hepatic arterial blood flow rates were determined simultaneously. In rats acetate is only intestinally produced and released into the portal vein. Intestinal production is decreased by 33% in starved and Paromomycin-treated rats compared to fed animals. Portal vein hepatic vein acetate differences are linearly related to the portal vein acetate concentration (r = 0.92). Acetate uptake from the portal vein by the liver was found when the portal venous concentration exceeded 180 mumol l-1. In humans the hepatic net acetate uptake from the portal vein/net acetate release into the hepatic vein, measured as mmol min-1, is linearly related to the portal vein acetate concentration (r = 0.96). The data indicate that the liver may homeostatically regulate the systemic acetate concentration in rat and man.     

Significance of aminopyrine breath test as a parameter of hepatic functional reserve in 40% partial hepatectomy of rats with CCl4-induced liver injury

Rats with CCl₄-induced liver injury underwent partial (40%) hepatectomy. The [¹⁴C]aminopyrine breath test (ABT) values in rats with CCl₄-induced liver injury were reduced by 34% compared with those in rats with normal liver. Preoperative ABT values clearly discriminated between survivors and those that died following 40% partial hepatectomy in rats CCl₄-induced liver injury (P<0.05). Hepatic protein synthesis was remarkably enhanced in CCl₄-induced liver injury compared with normal liver (P<0.001), and this was inversely correlated with ABT values (P<0.001). These data show that the enhanced hepatic protein synthesis could induce a decrease of hepatic functional reserve. ABT seems to be a useful preoperative test for predicting surgical mortality following hepatectomy.     

Alteration of drug metabolism during cholestasis in man.

The morphological and functional alterations of the smooth endoplasmic reticulum of the liver cell related to biliary stasis have brought attention to drug biotransformation during cholestasis. The metabolism of meprobamate, pentobarbital and tolbutamide was assessed in subjects with intrahepatic recurrent cholestasis (3), cholestatic hepatitis (6), extrahepatic biliary obstruction (7) and normal controls (16). In the patients with recurrent intrahepatic cholestasis no differences in drug metabolism were noted as compared to the control group. In cholestatic hepatitis the plasma half-lives of meprobamate (828 +/- 422 min.) and pentobarbital (39+-65) were significantly longer than in in controls (444 +/- 37 and 25.4 +/- 1.1 respectively). Tolbutamide plasma half-life appeared unchanged. The most striking variations were observed in the patients with extrahepatic biliary obstruction. In such cases while meprobamate half-life was unchanged, pentobarbital half-life was significantly prolonged (31.2 +/- 2.5) and the in vitro metabolism of the drug, using liver preparations, was decreased to less than 50% of the control value. In contrast the metabolism of tolbutamide was accelerated as evidenced by a significant decrease of plasma half-life (165 +/- 48 min. versus 384 +/- 76 of the controls) and an enhanced urinary excretion of the drug's metabolites. However the metabolism of tolbutamide in vitro did not show any difference between normal and cholestatic liver. Whatever the mechanism of the peculiar behaviour of tolbutamide in extrahepatic biliary obstruction it seems to be related to the increased bile dalt concentration during cholestasis. In fact the low values of plasma half-life increase significantly either relieving the biliary obstruction or producing a bile salt depletion with cholestyramine. Preliminary results in vitro suggest the bile salt could displace tolbutamide from albumin binding thus increasing the amount of free drug available for biotransformation by the liver. In conclusion cholestasis may affect drug metabolism depending on the degree of biliary stasis, liver cell injury and the type of drug tested. The mechanism could be that of an impaired biotransformation in the smooth endoplasmic reticulum or could involve extrahepatic factors.     

Effect of concomitant administration of cimetidine hydrochloride on the pharmacokinetic and safety profile of tamsulosin hydrochloride 0.4 mg in healthy subjects

Background: Tamsulosin is an α₁-adrenergic receptor antagonist that is metabolized primarily via the cytochrome P450 (CYP450) enzymes. Cimetidine hydrochloride is a histamine H₂-receptor antagonist that is known to inhibit the activity of CYP enzymes.Objective: The purpose of this nonrandomized, sequential, drug-drug interaction study was to determine whether concomitant administration of cimetidine affects the pharmacokinetic and safety profile of tamsulosin 0.4 mg in healthy subjects.Methods: In this 11-day study, 10 healthy subjects aged 21 to 38 years received a single daily dose of placebo except on study days 2 and 8, when they received tamsulosin 0.4 mg. From day 5 through day 10, subjects also received a single oral tablet of cimetidine 400 mg every 6 hours. Safety monitoring was performed throughout the study. Plasma tamsulosin concentrations were determined at regular intervals after administration of the drug on days 2 and 8, and tamsulosin pharmacokinetic parameters were tested for equivalence on these 2 days.Results: Oral clearance of tamsulosin was significantly reduced (P < 0.004), and area under the plasma concentration—time curve extrapolated to infinity (AUC_0−∞) significantly increased (P < 0.004) during concomitant administration of cimetidine. However, the observed increase in AUC_0−∞ was not expected to be clinically important since tamsulosin is well tolerated at twice the dose used in this study. Some significant changes in vital signs (ie, diastolic blood pressure <60 mm Hg) and a number of mild adverse events such as headache were observed, but the overall safety profile of tamsulosin plus cimetidine was acceptable.Conclusions: The results of this pharmacokinetic study were likely due to inhibition by cimetidine of CYP450 isozymes that catalyze tamsulosin metabolism. Although this study was conducted in young, healthy volunteers, thereby limiting the conclusions that can be drawn, the results, taken in the context of similar studies conducted in the target population, do not suggest that dose adjustment of tamsulosin is necessary in patients concurrently receiving cimetidine therapy.     

Genetic polymorphisms of drug metabolism

The molecular mechanisms of 3 genetic polymorphisms of drug metabolism have been studied at the level of enzyme activity, enzyme protein and RNA/DNA. As regards debrisoquine/sparteine polymorphism, cytochrome P-450IID6 was absent in livers of poor metabolizers; aberrant splicing of premRNA of P-450IID6 may be responsible for this. Moreover, 3 mutant alleles of the P-450IID6 locus on chromosome 22 associated with the poor metabolizer phenotype were identified by Southern analysis of leucocyte DNA. The presence of 2 identified mutant alleles allowed the prediction of the phenotype in approximately 25% of poor metabolizers. The additional gene-inactivating mutations which are operative in the remainder of poor metabolizers are now being studied. Regarding mephenytoin polymorphism, although the deficient reaction, S-mephenytoin 4'-hydroxylation, has been well defined in human liver microsomes, the mechanism of this polymorphism remains unclear. All antibodies prepared to date against cytochrome P-450 fractions with this activity recognize several structurally similar enzymes and several cDNAs related to these enzymes have been isolated and expressed in heterologous systems. However, which isozyme is affected by this polymorphism is not known. As regards N-acetylation polymorphism, N-acetyltransferases have been purified from human liver, specific antibodies prepared; it was observed that immunoreactive N-acetyltransferase is decreased or undetectable in liver of "slow acetylators". Two genes that encode functional N-acetyltransferase were characterized. The product of one of these genes has identical activity and characteristics as the polymorphic liver enzyme. Cloned DNA from rapid and slow acetylator individuals has been analyzed to identify the structural or regulatory defect that causes deficient N-acetyltransferase.     

Effects of reduced glutathione and n-acetylcysteine on lidocaine metabolism in cimetidine treated rats

Summary— The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N-acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (ip) (1 mmol/kg) 1 hour before treatment with cimetidine (0.5 mmol/kg) or saline, and 1 hr later all rats were injected ip with lidocaine (1 mg/kg). Blood samples were drawn 30 min after the lidocaine injection. MEGX and lidocaine serum concentrations were determined by means of fluorescence polarization immuno-assay using the TDX system. Cimetidine produced a decrease in MEGX levels (from 210 ± 18 to 164 ± 13 ng/mL) and a parallel increase in lidocaine levels (from 73 ± 22 to 172 ± 47 ng/mL), consistent with cytochrome P-450 3A inhibition. Both GSH and NAC produced a significant decrease in MEGX levels (151 ± 16 and 139 ± 14 ng/mL, respectively), but no significant increase in lidocaine levels were found. As compared to the cimetidine group, pre-treatment using either GSH or NAC with Cimetidine produced a marked decrease in lidocaine levels (37 ± 27 and 63 ± 28 ng/mL, respectively) and no modification of MEGX levels (155 ± 12 and 165 ± 22 ng/mL, respectively). These results suggest that GSH and NAC might accelerate the lidocaine metabolism while counteracting the inhibitory effect of Cimetidine.     

急性百草枯中毒致药物性肝病影响因素的分析

目的：观察比较分析急性百草枯中毒致药物性肝病的影响因素。方法：选择2008-01-2013-12入住我院急诊科的急性百草枯中毒患者112例,根据急性百草枯中毒致肝损伤的的诊断标准判断患者是否发生药物性肝病,分为损伤组和对照组,对患者性别、年龄、口服剂量、是否接受超早期洗胃治疗、是否接受早期血液灌流治疗、是否接受CRRT治疗等因素对百草枯所致药物性肝病的影响进行Logistic回归分析。结果：2组患者性别、年龄差异无统计学意义,Logistic回归分析发现口服剂量、是否接受超早期洗胃治疗、是否接受早期血液灌流治疗、是否接受CRRT治疗与急性百草枯患者肝损伤的发生可能存在相关性（P〈0.05）。结论：百草枯的口服剂量对肝功能损伤的影响最大,及时给予超早期洗胃治疗、早期血液灌流治疗能减少患者肝功能损伤的发生。     

Interspecies variability and drug interactions of clozapine metabolism by microsomes

Cytochrome P450 expression in liver is influenced by several factors, including species, sex and strain. We compared metabolism formation of clozapine in different species (rat, mouse, guinea-pig, dog, monkey and man) so as to choose between species to further validate interaction studies. Liver microsomes of male and female Sprague-Dawley rats, hairless rats, OF1 mice, Balb C mice and Dunkin-Hartley albino guinea-pigs, male beagle dogs, male cynomolgus monkeys and man were used to investigate in vitro metabolism of clozapine. This process was dependent on the presence of NADPH and on the presence of microsome protein. In addition, we observed the formation of desmethyl- and N-oxide metabolites, with the rate of formation of each of these compounds varying with species, sex and strain of microsomes incubated. The desmethyl- and N-oxide metabolites formed were statistically greater in male than in female rats, mice in the two strains studied, as well as for the guinea-pigs. Levels of desmethyl clozapine formed were high for the rats and no significant difference in clozapine biotransformation was observed between Sprague-Dawley and hairless rats. For man, the formation of metabolites of clozapine was comparable with guinea-pig, dog and monkey. In addition, we screened the effect of 52 molecules, representative of 11 different therapeutic classes, on the metabolism of clozapine by rat liver microsomes. We found that most of the calcium channel blockers (diltiazem, felodipine, isradipine, lacidipine, nicardipine and nitrendipine), antifungals (ketoconazole, miconazole) and two anticancer drugs (paclitaxel, teniposide) caused more than 50% inhibition of clozapine metabolism in vitro. The extent of inhibition was increased in a concentration-dependant manner. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.     

Ammonia and glutamine metabolism in human liver slices: new aspects on the pathogenesis of hyperammonaemia in chronic liver disease

Ammonia and glutamine metabolism was studied in slices from normal, fatty and cirrhotic human livers. The liver disease was evaluated by histological examination. With respect to ammonia removal, urea and glutamine synthesis in human liver represent low and high affinity systems with k0.5(NH4+) values of 3.6 and 0.11 mM, respectively. Compared with normal control livers, cirrhotic livers showed a decreased glutamine synthesis from NH4Cl by about 80%. The same was true for urea synthesis. Conversely, flux through hepatic glutaminase was increased in cirrhosis 4-6-fold. These changes in hepatic glutamine and ammonia metabolism were observed regardless of whether reference was made to liver wet weight, DNA or protein content. Acetazolamide inhibited urea synthesis in cirrhotic liver slices by about 50%, indicating that mitochondrial carbonic anhydrase is required for urea synthesis also in cirrhosis. There was a significant correlation between the in-vitro determined capacity for urea synthesis from NH4Cl and the in-vivo determined plasma bicarbonate concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

非酒精性脂肪性肝病与胰岛素抵抗及糖脂代谢关系的研究

目的:分析非酒精性脂肪性肝病(NAFLD)患者的肝脏脂肪含量与胰岛素抵抗(IR)、糖脂代谢间的关系。方法:收集19例NAFLD患者的临床资料,同时选择17例非NAFLD患者作为对照组,询问病史及体检,检测肝功能、血脂,行口服葡萄糖耐量试验(OGTT)并测各点血糖和胰岛素水平,采用磁共振及质子磁共振波谱(1HMRS)分析对肝脏的脂肪含量进行定量测检。结果:NAFLD组患者的肝丙氨酸氨基转移酶(ALT)、血三酰甘油(TG)、OGTT各点血糖、葡萄糖曲线下面积(AUCg)、OGTT0min胰岛素、OGTT120min胰岛素、早期胰岛素分泌(ΔI30/ΔG30)、稳态模型法评估胰岛素抵抗指数(HOMA-IR)均高于非NAFLD组(P<0.05),而其高密度脂蛋白-胆固醇(HDL-C)低于非NAFLD组(P<0.05)。NAFLD组中,11例糖代谢正常者与8例糖代谢异常者相比,两者间ALT差异无统计学意义,而糖代谢正常者的γ-谷氨酰转肽酶(GGT)较低,差异有统计学意义(P<0.05)。NAFLD糖代谢正常组GGT、TG、OGTT各点血糖及AUCg均低于糖代谢异常组(P<0.05),而其OGTT0min胰岛素、OGTT120min胰岛素有高于糖代谢异常组的趋势,但差异尚无统计学意义。结论:NAFLD患者存在明显的胰岛素抵抗(IR),其肝脏脂肪含量增加与IR明显相关,ALT为最早出现异常的指标。当NAFLD患者出现糖代谢异常后,则表现为胰岛β细胞分泌功能受损,胰岛素分泌量降低,GGT异常。因此,早期控制NAFLD,对保护患者的胰岛功能、改善其糖代谢异常有重要作用。     

Effects of treatment with chenodeoxycholic acid on liver microsomal metabolism of steroids in man

The present investigation was undertaken to evaluate whether treatment of gallstone patients with chenodeoxycholic acid is associated with changes of the hepatic metabolism of steroids. Altogether 37 patients with cholesterol gallstones undergoing cholecystectomy were included in the study. Nine of them had been treated with chenodeoxycholic acid (15 mg/kg/day) for about 8 weeks prior to operation. Two hydroxylations involved in cholic acid biosynthesis, 12 alpha-hydroxylation of 7 alpha-hydroxycholest-4-en-3-one and 25-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol, and the metabolism of a physiological steroid hormone, androst-4-ene-3, 17-dione, were studied in the microsomal fraction of liver homogenates. The 12 alpha-hydroxylase was inhibited about 50%, which is in accordance with a regulatory function of this enzyme. The 25-hydroxylase and the metabolism of androst-4-ene,3, 17-dione were unaffected. It is concluded that chenodeoxycholic acid treatment is not associated with general influences on hepatic steroid metabolism.     

2型糖尿病伴脂肪肝与瘦素及血脂代谢的相关分析

目的探讨2型糖尿病(DM)伴脂肪肝与瘦素及脂代谢紊乱的相关性.方法随机选择我院内分泌科200例2型糖尿病患者,其中合并脂肪肝组89例,非脂肪肝组111例,对其进行有关临床、病史、生化指标、瘦素、C肽与肝脏B超检查. 结果 2型糖尿病伴脂肪肝组与不伴脂肪肝组比较体质量指数(BMI) (27.68±4.00) vs(24.72±3.07)kg/m2、甘油三酯(TG)(2.88±3.19) mmol/L vs (1.74±1.18) mmol/L、1小时C肽(4.23±2.87) μg/L vs (2.32±1.97) μg/L、2小时C肽(4.43±2.93)μg/L vs (2.71±1.54) μg/L、瘦素(13.08±8.88) μg/L vs (8.63±5.45)μg/L,水平明显增高.Logistic逐步回归分析显示1小时C肽、瘦素、甘油三酯水平与脂肪肝的发生呈正相关(r=0.005、0.002、0.040).结论 TG、1小时C肽、瘦素是影响2型糖尿病脂肪肝发生的主要影响因素.