Placental transfer of pinazepam and its metabolite N-desmethyldiazepam in women at term

Summary Placental transfer of pinazepam and its metabolite N-desmethyldiazepam was investigated in 25 pregnant women at term. Pinazepam was administered orally as a single (10 mg) dose to 13 women, or in multiple doses of 5 mg daily to 12 women. The dose-delivery interval ranged between 1 and 26 h for the single dose, and the period between the last of the multiple doses and delivery was 1.4 to 24 h. Pinazepam and N-desmethyldiazepam were measured in plasma obtained from the umbilical vein and from the mother, at delivery. Pinazepam was only detectable in plasma after the 10 mg dose. The drug did not reach an apparent equilibrium between fetal and maternal plasma. The average (±SEM) cord/maternal ratio of plasma pinazepam concentrations was 0.64±0.07. N-desmethyldiazepam was detectable on each occasion. Its concentration in the plasma from the cord vein became higher than that in the maternal specimens 1–2 h after administration of the parent drug. Little N-desmethyldiazepam was excreted in breast milk.     

Placental transfer and distribution of pinazepam and its metabolite N-desmethyldiazepam in the maternal and fetal rabbit: effect of the stage of gestation

The distribution of pinazepam and its metabolite N-desmethyldiazepam was studied in fetuses of New Zealand rabbits on the 20th and 27th day of pregnancy. The concentrations of both compounds were also measured in the maternal brain, liver and uterus. Pregnant rabbits were sacrificed at 0.5, 2, 4 and 12 h after intravenous administration of pinazepam (5 mg/kg). The concentrations of pinazepam and N-desmethyldiazepam in various biological specimens were measured by a specific gas-chromatographic procedure. Pinazepam and N-desmethyldiazepam rapidly crossed the placenta. In 20 day old fetuses, comparable concentrations of pinazepam were found in the liver, brain, heart, lungs and kidneys. In contrast, the liver of 27 day old fetuses accumulated pinazepam at concentrations higher than the other tissues. The hepatic extraction of pinazepam, already described in adult rabbits (1), develops prenatally. A preferential accumulation of pinazepam rather than N-desmethyldiazepam was also observed in the maternal uterus. In this tissue the concentrations of pinazepam were 5-10 times higher on the 27th rather than the 20th day of pregnancy. The stage of pregnancy influences the distribution pattern of pinazepam in rabbit fetuses and their mothers.     

Disposition, distribution, plasma protein binding and biliary excretion of pinazepam after i.p. administration to rat

The pharmacokinetics, distribution, plasma protein binding and the biliary excretion of pinazepam were studied in the rat. The drug was administered (5 mg/kg) by i.p. injection. The chemical analysis of pinazepam and its metabolites was carried out by a gas-chromatographic method. The parent compound was rapidly absorbed, accumulated into the tissues and converted into N-desmethyldiazepam. The highest plasma levels of the parent compound (367 +/- 13 ng/ml) were found 3 min after administration. The volume of distribution and the clearance of the drug were 1315 ml and 7.23 ml/min respectively. The metabolite was detected in the plasma and tissues 3 min after administration. At this sampling time its concentrations were 76 +/- 16 ng/ml in the plasma and 1081 +/- 68 ng/g in the liver. The decay curve of both pinazepam and N-desmethyldiazepam in the plasma, liver, lung, heart, kidney, brain, and gastrochemius muscle were characterized for their Kel, t 1/2, and AUC values. The tissue AUC to plasma AUC ratios indicated a preferential accumulation of pinazepam over its metabolite in the tissues. The plasma protein binding of pinazepam was measured by dialysis at the equilibrium. Rat plasma proteins bound 89.17 +/- 0.20 percent of the drug. The association constant was 2.60 X 10(3) l/mole and the number of sites 0.44 X 10(-6) sites/g. The biliary excretion of pinazepam and N-desmethyldiazepam was poor.     

Pharmacokinetics of pinazepam in healthy volunteers

The kinetics of pinazepam were studied in six healthy male volunteers aged between 26 and 31 years. The drug was administered in a single oral dose (10 mg). The concentrations of the parent compound and metabolites were measured in the plasma and urine by gas-chromatographic analysis. Plasma levels of pinazepam were fitted to a two-compartment open model with first order absorption rate using a three-exponential equation. Absorption rate constant and peak plasma levels of pinazepam were 1.36 +/- 0.15 h-1 and 36.8 +/- 5.1 ng/ml respectively. Plasma decay of the drug consisted of an initial rapid elimination phase (alpha = 0.46 +/- 0.06 h-1) followed by a slow one (beta = 0.046 +/- 0.004 h-1). N-desmethyldiazepam was the only metabolite detected in the plasma. Its plasma concentrations were higher than those of the parent compound shortly after administration. Urine was collected for 72 h after dosing. Those specimens contained unconjugate pinazepam and N-desmethyldiazepam and glucuronated oxazepam and 3-OH-pinazepam. Only 0.016% of the pinazepam administered was recovered as unchanged compound in the urine.     

The psychopharmacological properties of pinazepam, a new benzodiazepine derivative.

The pharmacological differences between the behavioural effects of 7-chloro-1-propargyl-5-phenyl-3H-1,4-benzodiazepin-2-one (pinazepam) and diazepam were investigated in rats. Pinazepam was more than twice as active as diazepam at a dose range between 1.25--10 mg/kg in reducing the conditioned emotional response (CER). Only at doses of 2.5 and 5 mg/kg prevented pinazepam the disruption of the avoidance responses induced by inverting the conditioned stimulus (CS). On the other hand pinazepam was less active than diazepam in reducing the number of avoidance responses in a conditioned avoidance situation. Neither pinazepam nor diazepam disrupted the conditioned responses in a fixed-interval operant behaviour.     

Toxicological and pharmacological investigations of pinazepam (7-chloro-1-propargyl-5-phenyl-3H-1,4-benzodiazepin-2-one): a new psychotherapeutic agent.

The pharmacological and toxicological properties of 7-chloro-1-propargyl-5-phenyl-3H-1,4-benzodiazepin-2-one (pinazepam) were investigated and compared with those of diazepam. In mouse and rat acute toxicity, in rat motor coordination and in rat metrazol convulsion tests pinazepam was compared with oxazepam too. Pinazepam, which is characterized by the presence of a propargylic side chain, showed a lower toxicity, hypnotic activity and muscular-relaxant activity than diazepam. Pinazepam and diazepam showed, however, similar activity in reducing aggressive behaviour in mice, stimulating the exploratory behaviour in rats and in potentiating hexobarbital narcosis. No clear-cut differences were observed in the anticonvulsant properties of the two drugs when tested against metrazol, strychnine and electroshock induced seizures. Pinazepam differs from diazepam for its longer duration of action. The main metabolic product found in the urine of rats and dogs treated with pinazepam was oxazepam.     

Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac

Purpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (F_H) of diclofenac was estimated to be 63%.     

The formation, disposition, and hepatic metabolism of dimethylnitrosamine in the pig

The disposition, metabolism, and endogenous formation of N-nitrosodimethylamine (NDMA) from nitrosatable precursors was studied in the intact pig and in animals with cannulated hepatic and portal veins and catheterized bile ducts. Rates of disappearance of NDMA from peripheral venous and arterial blood after iv injections were virtually identical and the compound appeared in bile after a lag time of about 1 hr, with a subsequent decline in biliary concentration at about the same rate as in circulating blood. Measurements of NDMA in portal and hepatic vein blood after oral doses of 10, 1.0 and 0.1 mg/kg, respectively, showed progressively greater hepatic extraction with levels in the hepatic vein approaching the limits of detection after the lowest dose. Both halothane and ethanol virtually abolished the hepatic extraction of NDMA, presumably due to their known inhibitory action on its metabolism in the liver. Endogenous formation of NDMA and N-nitrosomorpholine after oral doses of the amines plus nitrite was demonstrated by their detection and measurement in the portal vein blood. Morpholine was nitrosated more effectively than dimethylamine and inhibited the nitrosation of the latter when the two amines were given together. NDMA was found in the portal blood after sequential oral administration of aminopyrine and nitrite, the concentration being considerably greater after fasting for 24 hr than after a 2-hr fast when much food was present in the stomach.     

彩色多普勒在无损伤性肝循环中的应用

本研究应用彩色多普勒超声对于３０例正常肝脏，３０例慢性肝病，２５例肝硬化，２２例原发性肝癌症的门静脉，脾静脉及肝静脉进行多种数据测量。结果显示慢肝时门脉血流量显著少于正常，慢肝，肝硬化，肝癌时门脉内径明显增宽，血流速度明显减低，肝静脉内径变窄，最大流速比平均流速增高显著，充血指数小于正常、笔者认为，应用彩色多普勒为无创伤性测量肝脏循环确定一种新的诊断标准，门脉血流量的测定，可作为慢肝和肝硬化的鉴别     

Arterial-venous blood alcohol concentration gradients

Arterial and venous blood alcohol concentration (BAC)-time courses were completely defined in the peripheral circulations, both during and after the constant rate infusions of ethanol via the cephalic vein or hepatic artery in the dog. These BAC data were characterized by the following trends. (1) A much faster rise in the blood alcohol curve, as well as a higher peak BAC was found using the shorter infusion time. (2) During infusion, the alcohol concentration was higher in arterial or arterialized blood than venous blood when infusion was via the cephalic vein. (3) Peak BAC was higher in the femoral artery than the femoral vein whether infusion was via the cephalic vein or hepatic artery. (4) Peak BAC was higher in the hepatic artery or portal vein than the hepatic vein when infusion was via the cephalic vein. When administration was directly into the liver, the peak BAC in the hepatic vein was higher than the portal vein. (5) After infusion ceased, there was an arterial-venous inversion; peripheral arterial ethanol concentrations were significantly less (p<0.001)than corresponding venous concentrations; with cephalic vein administration, a hepatic vein-portal crossover was observed, the reverse being true when ethanol was administered via the hepatic artery. In either case, the BAC was observed to be higher in the hepatic artery than the portal vein or hepatic vein throughout the sampling period. (6) BAC was observed to be higher for the same sampling times at the respective sites when ethanol was administered directly into the liver. While the methodology in this study is prohibitive for human experimentation, correlations may be extended to man. The elaboration of the arterial-venous concentration differences for ethanol should prove beneficial in revealing the relationships among the doses of alcohol, the circulating blood ethanol concentrations, and physiological and psychomotor test parameters in man.This work was supported in part by a grant from The University of Connecticut Research Foundation.Abstracted in part from a dissertation by J. L. Rheingold submitted to The University of Connecticut in partial fulfillment of the Doctor of Philosophy degree requirements.     

NO和iNOS在肝硬化患者肝组织中的表达及与门静脉压力的关系

目的：观察NOS-NO系统在肝硬化患者肝组织中的表达及与门静脉压力的关系，以探讨其在肝硬化门脉高压中的作用。方法：随机抽取20例正常志愿者及20例肝硬化患者，在B超引导下经皮经肝穿刺分别测定门静脉压力、抽取门静脉血和外周血并留取肝组织，测定血液中NO浓度，观察肝组织iNOS的表达。结果：肝硬化患者下腔静脉及门静脉血中NO浓度、肝组织iNOS的表达及门静脉压力均分别显著高于正常对照组。正常对照组的外周血和门静脉血中NO浓度水平接近．差异无统计学意义；但肝硬化患者的门静脉血NO浓度显著高于外周血NO浓度。门静脉压力与外周静脉血NO浓度、门脉血NO浓度及肝组织中iNOS的表达呈直线相关关系。结论：门静脉压力与门脉血NO浓度、肝组织中iNOS的表达密切相关。     

Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine

PURPOSE: Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance. METHODS: Rat livers were implanted with Walker-256 tumors. The tumor-bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR-1065 concentrations in the blood, liver and tumor were measured at various times. RESULTS: The WR-1065 tumor portal dosing AUC15-60 was 40% of systemic dosing, and tumor concentrations following portal dosing were one-fifth of that following systemic dosing. The portal dosing WR-1065 liver AUC15-60 was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR-1065 following portal dosing were up to 8-fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR-1065 was greater following portal vs systemic amifostine. CONCLUSIONS: Amifostine may provide increased liver protection and decreased tumor protection from radio- or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR-1065, which is associated with hypotension.     

Tissue extraction of amiodarone and N-desethylamiodarone in man after a single oral dose.

The hepatic extraction of amiodarone and N-desethylamiodarone has been investigated in seven patients following catheterization of the portal and hepatic veins under general anaesthesia. Amiodarone (600 mg) was administered orally 4 h before regional blood sampling. Concentrations of amiodarone and N-desethylamiodarone, determined by h.p.l.c., were about twice as high in the portal vein compared with those in the hepatic vein, the calculated hepatic extraction ratios of both compounds being 0.39 +/- 0.07 and 0.34 +/- 0.03, respectively. The presence of N-desethylamiodarone in the portal vein in higher concentrations than in the hepatic vein strongly suggests that N-dealkylation of amiodarone occurs in the gut wall or lumen, a finding which might account for the low and highly variable intersubject amiodarone bioavailability.     

Phenacetin concentrations in portal and hepatic venous blood in man.

After intra-gastric or intra-duodenal administration of phenacetin (200 mg in solution), concentrations of phenacetin and its 0-dealkylated metabolite, acetaminophen, in portal and hepatic veins and in peripheral blood were monitored. A sharp increase in the portal concentration of phenacetin indicated rapid absorption. The concentration ratio of acetaminophen to phenacetin in early portal blood was 0.01--0.11 and lower than the ratio in hepatic vein. The hepatic extraction ratio of phenacetin was calculated to be 0.59--0.78. It is concluded that 0-dealkylation occurs mainly in the liver and only to a limited extent in the gastrointestinal wall.     

Hepatic presystemic elimination of diethylstilbestrol by rats and effect of pretreatment with inducers of UDP-glucuronosyltransferase

In order to determine if the synthetic estrogen diethylstilbestrol (DES) undergoes hepatic presystemic elimination, male Sprague-Dawley rats were administered [3H]DES (0.005, 0.05, 0.5 mg/kg) into either the ileocolic (portal administration) or femoral (systemic administration) vein. Plasma and bile samples were collected and the concentrations of both DES and DES glucuronide fractions were determined. The concentration of the DES fraction was lower and the proportion of glucuronides was higher after portal than after systemic administration of all three doses. Comparison of the areas under the curve (AUC) of plasma concentration versus time for the DES fraction indicates that the liver diminishes this fraction by 50-70%. Biliary excretion of DES also showed route-dependent differences, in that it was higher for 10-20 min after portal than after systemic administration. To determine if these effects could be enhanced by induction of UDP-glucuronosyltransferase, rats were pretreated for 4 d with phenobarbital, 3-methylcholanthrene, or pregnenolone-16 alpha-carbonitrile and then administered DES (0.5 mg/kg) by the portal or systemic route. 3-Methylcholanthrene and pregnenolone-16 alpha-carbonitrile enhanced the plasma disappearance of the DES fraction to a greater extent after portal than systemic administration and thus further increased the apparent hepatic presystemic elimination. This effect does not appear to involve increased glucuronidation or biliary excretion. These data provide evidence that hepatic presystemic elimination of DES occurs in rats, and this effect can be enhanced by some microsomal enzyme inducers.     

Regional pharmacokinetics of amifostine in anesthetized dogs: role of the liver, gastrointestinal tract, lungs, and kidneys.

Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 micro mol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8-3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation.     

An isolated dual-perfused rabbit liver preparation for the study of hepatic blood flow regulation.

An original, isolated dual-perfused rabbit liver preparation was developed for investigations into mechanisms that control the hepatic vascular tone. The hepatic artery (HA) and portal vein (PV) were perfused at constant flows of 0.16 +/- 0.01 and 0.64 +/- 0.05 mL/g/min (n = 5), respectively. Responses of the hepatic arterial and portal venous vascular beds to noradrenaline (NA) were measured as changes in perfusion pressure. Noradrenaline injected directly into the hepatic artery and portal vein produced dose-dependent increases in pressure in the respective vascular beds, the maximum response in the hepatic arterial bed being two to three times greater than that in the portal venous bed. A restricted transmission of vasoconstrictor stimulus between the intrahepatic portal venous and hepatic arterial vasculature was demonstrated. The results demonstrate the suitability of the dual-perfused rabbit liver model for detailed studies of the control of hepatic vascular tone.     

Subcellular distribution of pinazepam and its metabolite N-desmethyldiazepam in rat liver

The distribution in subcellular fractions of pinazepam (Pz) and its metabolite N-desmethyldiazepam (N-Dz) was studied after a single oral administration of Pz (20 mg/kg body wt) to rats. Animals were killed 2 min and 6 hr after dosing. The amounts of the parent drug and its metabolite retrieved in the microsomal fraction were small, but significantly higher than those in the nuclear, mitochondrial and soluble fractions. The cytosol contained the lowest percentages of both drugs. No substantial difference was found in the subcellular distribution pattern of both Pz and N-Dz 2 min and 6 hr after administration.     

Fundamental studies on excretion of pivmecillinam in bile (author's transl)

Excretion of pivmecillinam (PMPC) in bile was investigated using normal and hepatic disorder (intramuscular injection of carbon tetrachloride, 0.5 g/kg twice) rabbits. Bile and blood were collected hourly (0.5 approximately 8 hours) and both concentrations and rates between both (passage), and excretion rates were investigated. Ampicillin (AMPC) was chosen as a control drug. 1. When PMPC was given orally to the normal rabbit in a dose of 200 mg/kg, a bile concentration after 0.5 hour was 138.08 microgram/ml and a peak value was attained. The rate to plasma concentration was 22.67. An excretion rate was 0.224%. When PMPC was given orally to the hepatic disorder rabbit in a dose of 200 mg/kg, a bile concentration after 0.5 hour was 26.67 microgram/ml. A peak value of 28.87 microgram/ml was attained after 4 hours. Their rates to plasma concentrations were 13.27 and 8.02, respectively. An excretion rate was 0.058%. Bile and plasma concentrations, rates of bile to plasma and excretion rates of the hepatic disorder group were lower than those of the normal group. Disturbances of hepatic functions were checked by biochemical tests, i.e. GOT, and so on. 3. When ABPC as a control drug was given orally to the rabbit in a dose of 200 mg/kg, plasma concentrations of hepatic disorder group were higher than those of the normal group, but rates of bile to plasma concentrations and excretion rates of the hepatic disorder group were lower than those of the normal group. 4. Bile concentrations and excretion of PMPC were significantly higher than those of ABPC in the normal group. In the hepatic disorder group, however, no statistical difference was observed between them.     

高效液相色谱法测定直肠癌术中区域化疗血液、盆腔液和组织5-氟尿嘧啶浓度

目的:测定直肠癌术中区域化疗血液、盆腔液和组织5-氟尿嘧啶浓度。方法:20例直肠癌患者术中行区域化疗,注药后2、5、10、20、30、60min采集门静脉血、周围静脉血、盆腔液和癌旁组织,以高效液相色谱法测定5-氟尿嘧啶浓度。结果:各样本注药后2min即出现峰浓度,此后逐渐降低。其中,盆腔液浓度最高,癌旁组织最低,门静脉血药浓度高于周围静脉血。结论:直肠癌术中区域化疗,可使盆腔液、门静脉血和癌旁组织维持高的药物浓度,这对预防直肠癌术后局部和肝脏转移有指导意义。