Disposition of enalapril in the perfused rat intestine-liver preparation: absorption, metabolism and first-pass effect

A new procedure, namely the in situ perfused rat intestine-liver preparation, was introduced to examine the roles of the intestine and the liver in the elimination of enalapril, a new angiotensin-converting enzyme inhibitor. The in situ perfused rat intestine preparation was used to determine the rate and extent of enalapril absorption after an-intraduodenal dose. In the former technique, enalapril in blood perfusate (10 ml/min) was delivered via the superior mesenteric artery into the once-through perfused rat intestine-liver preparation, with sampling effected in reservoir, portal vein and hepatic vein. The ease of sampling, proximal and distal to the intestine and liver, allowed the direct estimation of the extraction ratios by the intestine and the liver. The steady-state intestinal extraction ratio of enalapril was small (0.04 +/- 0.066) compared to that for the liver (0.74 +/- 0.06), indicating that the liver was responsible for most of the hydrolytic conversion of enalapril to its pharmacologically active diacid metabolite, enalaprilat. Moreover, no trend in the values of the extraction ratios by both organs was apparent among the input concentrations of enalapril (0.55, 2.6 and 13.3 microM) used. Portal venous plasma consisted mainly of enalapril and was devoid of enalaprilat, whereas both enalapril and enalaprilat were detected in bile and hepatic venous plasma. With the latter technique, an intraduodenal injection of a tracer dose of [14C]enalapril (0.14-0.39 mumol) was made close to the pyloric sphinctor, whereas the intestine preparation was recirculated (7.5 ml/min) with blank perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Avoidance of "first-pass" elimination of rectally administered lidocaine in relation to the site of absorption in rats

The extent of "first-pass" elimination of lidocaine in relation to the site of absorption in the rectum of rats was investigated. Male Wistar rats received lidocaine orally, i.v. or rectally at 4, 2, 1 and at about 0.2 cm from the anus. In all cases 5.0 mg of a tritium-labeled lidocaine solution was administered by zero-order infusion into the rectum. In blood, unchanged lidocaine and urine and feces total radioactivity were measured. Lidocaine was absorbed almost completely in all cases as assessed relative to i.v. administration. The average elimination half-life was about the same for all routes of administration (approximately 27 min). Systemic availability of lidocaine when given by the oral route was 16%; a similar value was found after rectal administration at 4 cm distance from the anus. At 2 cm distance from the anus the mean systemic availability was 21%, at 1 cm, 45% and as closely as possible to the anus, 72%. It is concluded that the degree of avoidance of first-pass elimination of rectally administered lidocaine is very much dependent on the site of drug administration. When the drug is absorbed very closely to the anus, little first-pass elimination occurs.     

Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect

The effects of neomycin and cholestyramine on the disposition of lorazepam was examined in seven healthy drug-free men. Half-life as determined for the oral route was, in all subjects, 15% to 35% less than that determined for the intravenous route. Free oral clearance was slightly but not significantly less than free systemic clearance, but the ratio of the AUC of lorazepam glucuronide corrected for dose was twofold greater by the oral route. Urinary recoveries also differed (71.6% and 50.4%, oral versus intravenous). Neomycin and cholestyramine treatment resulted in a 19% to 26% reduction in half-life attendant on a 34% increase in free oral clearance and a 24% increase in free systemic clearance. This suggests that lorazepam undergoes significant enterohepatic recirculation in human beings and that there exists an extrahepatic pathway, at least for the intravenous route. Since pharmacokinetic measurements do not take these physiologic processes into account, the drug cannot properly be used as a marker of conjugative metabolism.     

Effect of ether or ketamine anesthesia on rat uterine estrogen and progesterone receptors

Rat uterine estrogen receptors (ER) and progesterone receptors (PR) have been used as controls in ER and PR assays of breast tumors. Stunning or decapitation of experimental animals without prior anesthesia is no longer acceptable as a method of killing. Thus, we compared the effects of two anesthetics on the concentration of rat uterine ER and PR. Rats were killed by one of three methods: (a) stunning, (b) ether anesthesia followed by decapitation, or (c) ketamine anesthesia followed by decapitation. ER and PR concentrations were determined by titration assay, with dextran-coated charcoal separation, and quantified by Scatchard analysis. No significant differences were found in mean receptor concentrations or dissociation constants for the three groups. The results indicate that there is no residual effect of diethyl ether or ketamine hydrochloride on the binding of either estrogen or progestin to their respective receptors. The use of decapitation after either ether or ketamine anesthesia is appropriate for measuring ER and PR receptors in rat uteri.     

Rectal bioavailability of lidocaine in man: partial avoidance of "first-pass" metabolism.

It is often speculated that after rectal administration drugs will enter the systemic circulation without first passing through the liver, because at least the lower hemorrhoidal veins are not connected to the portal system. To test this hypothesis, the systemic availability of the high-clearance drug lidocaine was investigated in 6 healthy subjects following administration of 200 mg intravenous, 300 mg oral, and 300 mg rectal lidocaine in a balanced crossover design. Plasma and whole blood concentrations of lidocaine were measured by capillary gas chromatography. The mean rectal systemic availability was higher than the oral: 63% vs 31% (whole blood) and 71% vs 34% (plasma). The elimination half-lifes (t1/2els) lidocaine were about the same intravenously and orally, whereas these were slightly longer after rectal administration. The oral and rectal investigations were repeated in the same panel of volunteers about 6 mo later. The mean rectal systemic availability, based on plasma concentrations, was then 67% vs 27% orally. Intraindividual variability was rather small, indicating that oral and rectal bioavailability of lidocaine is reproducible in individuals. An equation was derived for the calculation of the fraction of the dose given rectally that bypasses the liver after absorption which is slightly more than half the dose, assuming that dose is 100% absorbed. This investigation indicates that in principle it is possible to avoid, at least partly, drug loss caused by "first-pass" metabolism by giving the drug rectally.     

麻醉方法对大鼠生理、血气及血液流变学的影响

目的比较不同麻醉方式对大鼠生理、血气及血液流变学的影响,完善血液代用品标准评价模型的制备。方法 Wistar大鼠(16只)随机分为2组,分别采用戊巴比妥钠腹腔注射和乌拉坦肌肉注射的方法麻醉。记录麻醉起效时间,每隔5 min记录各项生理指标,直至术后40 min,随后抽血检测血气、血细胞及各项流变学参数。结果戊巴比妥钠组和乌拉坦组麻醉起效时间分别约为3.67和31 min,戊巴比妥钠腹腔注射起效显著快于乌拉坦肌肉注射(P<0.01);相对于戊巴比妥钠组,乌拉坦组降低平均动脉压(5、15、30、35、40 min)、收缩压(35、40min)、舒张压(15、30、35、40 min)、脉压差(40 min)和体温(除5 min时间点外),均为P<0.05;术后40 min,乌拉坦组Hct高于戊巴比妥钠组(P<0.05),pH明显降低(P<0.01),血浆粘度降低(P<0.05)。结论乌拉坦肌肉注射麻醉影响大鼠生理、血气分析和血液流变学指标,在进行药效评价时需慎重选择。     

腰麻和硬膜外麻醉对手术患者血液流变学的影响比较

目的比较腹部以下手术腰麻和硬膜外麻醉在术中对患者血液流变学的影响。方法选取美国麻醉协会标准（ASA）Ⅰ-Ⅱ级择期手术的患者78例，随机分为两组：A纽为腰麻组，经常规的消毒铺巾穿刺置管后给予0．75％布比卡因1．8ml；B组为硬膜外麻醉组，经常规的消毒铺巾穿刺置管后，硬膜外给罗哌卡因15～20d，术中每隔50min硬膜外给罗哌卡因5～7ml；A组术后肌注哌替啶镇痛，B组术后24h内用0．5％的罗哌卡因镇痛。分别于麻醉前、麻醉后30min、60min、90min各取桡动脉血5～10ml，测血液流变学指标。结果两组麻醉后30min全血高切及低切黏度、血细胞比容及红细胞聚集指数下降（P〈0．05），但B组这几项指标下降明显且持续时间长，且有血浆黏度及纤维蛋白原浓度的下降（P〈0．05）。结论腰麻有利于保持在术中对患者血液流变学的平稳，而硬膜外阻滞对血液流变学的影响更有利于预防术后患者下肢静脉血栓形成。     

Disposition kinetics of propranolol isomers in the perfused rat liver

The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)-propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S()-propranolol differs from the R(+)-isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.     

Disposition of beta-glucuronidase-resistant "glucuronides" of valproic acid after intrabiliary administration in the rat: intact absorption, fecal excretion and intestinal hydrolysis

The major metabolite of valproic acid (VPA) is its beta-glucuronidase-susceptible glucuronide conjugate (VPA-G). At slightly alkaline pH such as in bile, VPA-G undergoes intramolecular rearrangement into at least six beta-glucuronidase-resistant isomers (VPA-G-R). The in vivo disposition of VPA-G-R was compared with those of VPA-G and VPA, each at 100 mg of VPA per kg, after intrabiliary administration to surgically prepared rats fasted during the experiments. Administered VPA was rapidly and completely absorbed into blood (peak 30 micrograms of VPA per ml at 0-2 hr). Administered VPA-G was predominantly hydrolyzed (beta-glucuronidase) in the intestine and liberated VPA absorbed into blood (peak 5 micrograms of VPA per ml at 6-9 hr). Administered VPA-G-R was disposed along at least three pathways: (1) part excretion, mainly unchanged, in feces (12% of dose); (2) part absorption (intact) from gut to blood and excretion in urine as VPA-G-R (3.6% of dose); and (3) part hydrolysis in the intestine (most likely by nonspecific esterases) with absorption of liberated VPA into blood (peak 2 micrograms of VPA per ml at 12-24 hr). The VPA/VPA-G/VPA-G-R composition of recovered dose in bile and urine was determined after all doses. In fed, nontraumatized rats given VPA-G-R p.o. at 100 mg of VPA per kg, 50% of the dose was recovered (mainly unchanged) in feces, a portion was absorbed intact into blood (2.5% of dose VPA-G-R excreted in urine) and the remainder hydrolyzed in the intestine with absorption of liberated VPA into blood.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity

BACKGROUND AND OBJECTIVES: Systemic clearance of the opioid alfentanil after intravenous administration is an excellent in vivo probe for hepatic cytochrome P4503A (CYP3A) activity and drug interactions. Alfentanil effect (miosis) is a surrogate for plasma alfentanil concentrations, and alfentanil effect kinetics may be a suitable noninvasive probe for hepatic CYP3A. Oral alfentanil might be a probe for first-pass CYP3A activity; however, it is not used clinically, and oral alfentanil disposition is unknown. This investigation evaluated the disposition and miotic effects of oral alfentanil. METHODS: Ten healthy volunteers were studied in a dose-escalation fashion, receiving 23, 30, 43, and 75 microg/kg oral alfentanil on different days. Dark-adapted pupil diameter was measured at the time of venous blood sampling. Alfentanil was quantified by liquid chromatography-mass spectrometry. Plasma concentrations of alfentanil and pupil diameter change versus time data were analyzed by noncompartmental modeling. RESULTS: Alfentanil was rapidly absorbed (time to maximum concentration [T(max)], 0.7 +/- 0.5 hour). Mean values for area under the plasma concentration-time curve extrapolated to infinity (AUC( infinity )) (27 +/- 14, 38 +/- 22, 57 +/- 31, and 105 +/- 59 ng x h x mL(-1)) and maximum concentration (16 +/- 8, 23 +/- 16, 31 +/- 18, and 50 +/- 22 ng/mL) were linear with dose, although there was considerable interindividual variability. T(max), elimination half-life (1.0 +/- 0.2 hours), total body clearance after oral administration (20 +/- 18 mL x kg(-1) x min(-1)), and dose-normalized AUC(infinity ) were independent of dose. Dose-dependent alfentanil disposition was mirrored by commensurate changes in clinical effect, although miosis was variable and not detectable in all subjects at the lowest dose. Mean miosis AUC (AUEC) and peak miosis were log-dose linear. Effect half-life (1.3 +/- 0.9 hours) was similar to plasma half-life. CONCLUSION: Oral alfentanil is rapidly absorbed, exhibits linear and dose-independent kinetics, and undergoes substantial first-pass metabolism. Oral alfentanil may be a suitable probe for first-pass CYP3A activity. Alfentanil effect (miosis) may be an acceptable surrogate for plasma alfentanil concentrations. Oral alfentanil effect may be a noninvasive surrogate for conventional pharmacokinetics. Further studies are warranted to determine whether oral alfentanil and alfentanil effect kinetics may be a suitable noninvasive in vivo probe for first-pass CYP3A activity.     

Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery.

The pharmacokinetics of hexobarbital were studied in 13 patients with acute hepatitis. Hexobarbital sodium was administered by zero order intravenous (iv) infusion, and plasma concentrations were determined regularly by gas chromatography. For each patient the data were fitted according to 2-compartment kinetics. The results were compared to those obtained for 14 healthy volunteers. The elimination half-life of hexobarbital was 490 +/- 186 min in the hepatitis patients and 261 +/- 69 min in the control group. Clearance was significantly reduced in the hepatitis group, whereas the volume of distribution at steady state was not significantly altered. For some patients the initial distribution volume was reduced. In 6 patients the experiment with hexobarbital was repeated after apparent recovery from hepatitis as judged by normal transaminase and bilirubin levels. Generally the half-life of hexobarbital was shorter and the clearance value was higher than during the acute illness, but the values had not yet returned to normal. Clinical recovery from liver disease is not accompanied by corresponding recovery of drug-metabolizing capability.     

过氧化氢杀菌试验中泡沫的影响及试验方法的研究

摘要 目的 〖JP2〗研究杀菌试验中产生的泡沫对过氧化氢消毒液杀菌效果的影响及其试验方法。方法 通过比较载体定量杀菌实验和悬液定量杀菌实验的方法,对实验中产生的泡沫影响过氧化氢消毒液杀菌的效果进行观察。结果 不锈钢片载体法定量杀菌试验中,过氧化氢消毒液能与目标细菌充分接触和作用,可以避免泡沫的影响,能准确评价常用浓度过氧化氢消毒液的杀菌性能。而布片、纸片载体可吸附大量气泡,悬液试验同样产生气泡影响试验效果。结论 针对某些易被触酶分解产生泡沫的过氧化氢消毒剂,采用不锈钢菌片浸泡定量杀菌试验法评估其杀菌效果。〖JP〗