Disposition and pharmacokinetics of naltrexone after intravenous and oral administration in rhesus monkeys

The purposes of this investigation were to determine the disposition of naltrexone (NTX) in monkeys and assess the role of first-pass metabolism and enterohepatic cycling in the disposition process. Concentrations of naltrexone and three metabolites were determined in plasma and urine as a function of time after po and iv NTX administration in six monkeys. Urinary recovery of NTX and metabolites 0-48 hr after iv administration (10 mg/kg) totaled 52% of the dose. Recovery in feces was minimal. Total urinary excretion of NTX and metabolites after po administration was 89% of that after iv administration, suggestive of good absorption of NTX from solution. However, the area under the plasma level-time curve for NTX after po administration was only 3.6% of that after iv administration, indicating a very high first-pass effect. The calculated extraction ratio was 0.96-0.99. Analysis of plasma level-time and urinary excretion rate-time data for NTX, conjugated NTX, beta-naltrexol, and conjugated beta-naltrexol after iv administration revealed that 1) the decline of plasma levels or urinary excretion rates with time for the conjugated metabolites was parallel to the decline for the apparent precursor; 2) the decline of plasma levels or urinary excretion rates for beta-naltrexol was slower than for naltrexone; and 3) there is evidence for a pronounced enterohepatic cycling of conjugated NTX and conjugated beta-naltrexol that influences the plasma level-time profile of these conjugates and the unconjugated compounds as well.     

Salivary excretion of mexiletine after bolus intravenous administration in rats.

Salivary excretion of mexiletine was investigated following bolus intravenous administration (10 mg kg-1) in rats. Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (3 mg kg-1 h-1). The mexiletine levels in blood plasma and parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva. Significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (P less than 0.001). The saliva/plasma drug concentration ratios (S/P ratios) did not vary to a large extent (0.56 +/- 0.10 for parotid saliva, 0.21 +/- 0.06 for mandibular saliva), but there was a consistent tendency for the higher plasma drug levels in the distribution phase to produce relatively high S/P ratios for both parotid and mandibular saliva. Moreover, the plasma mexiletine levels calculated by the equation of Matin et al (1974) employing the observed values for the saliva drug level, saliva pH and free fraction of mexiletine in plasma were significantly higher than the observed drug levels. Therefore, it is suggested that the salivary excretion of mexiletine could not be explained quantitatively by simple, passive secretion based on pH-partition theory.     

Metabolism and disposition of naltrexone in man after oral and intravenous administration

The metabolism and elimination of [15, 16,-3H2]naltrexone was studied in man after oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and conjugated and unconjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely absorbed after oral administration. After oral and intravenous administration of naltrexone, about 60% of the dose was recovered in the urine in 48 and 72 hr, respectively. The route of administration did not significantly affect urinary clearance values obtained for unconjugated or conjugated naltrexone and 6 beta-naltrexol. The route of administration significantly affected terminal plasma half-life values obtained for unconjugated naltrexone (2.7 hr, iv; 8.9 hr, oral), but had little effect on comparable values obtained for total drug, conjugated naltrexone, and unconjugated and conjugated 6 beta-naltrexol. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol, and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine.     

Pharmacokinetics of aminolevulinic acid after oral and intravenous administration in dogs.

The purpose of these studies was to examine the pharmacokinetics, oral bioavailability, and systemic side effects of aminolevulinic acid (ALA) in beagle dogs after oral and i.v. administration. Oral and i.v. doses of ALA (128 mg of ALA hydrochloride, equivalent to 100 mg of ALA) were administered to four animals using a crossover design. Animals were allowed a 2-week washout period between doses. Plasma ALA concentrations were determined using precolumn fluorescent derivatization and reversed-phase HPLC. Plasma concentrations after i.v. administration declined rapidly with a terminal half-life of 19.5 +/-2.5 min (mean +/- S.D.). Total body clearance and volume of distribution at steady state averaged 6.79+/-1.77 ml/min/kg and 259+/- 128 ml/kg, respectively. Peak plasma concentrations of ALA after oral administration ranged from 1.27 to 9.42 microgram/ml. Oral bioavailability in these animals averaged 41.2+/-14.8% (range, 23.5-58.5%). These studies demonstrate that oral administration may provide a convenient and efficient route of delivery of ALA for photodynamic therapy in patients.     

Plasma timolol levels after oral and intravenous administration

Summary The plasma kinetics of timolol administered orally and intravenously to 5 male subjects were examined. Bioavailability was reduced by 25% when the drug was taken orally. Mean plasma half-life after oral dosing was 4.86 h, and after intravenous administration it was 4.56 h; the difference was not significant. The volume of distribution was 3.5 l/k. It is suggested that timolol is little affected by the first pass effect, even though there is marked interindividual variation in availability and peak plasma level.     

Disposition of a new diacid angiotensin-converting enzyme inhibitor after intravenous administration of drug or prodrug to monkeys and dogs.

The disposition of [4S-[4 alpha,7 alpha,(R*),12b beta]]-7- [S-(1-carboxy-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6- oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid (MDL 27,088), a new a new angiotensin-covering enzyme inhibitor, was studied in cynomolgus monkeys and beagle dogs given intravenous (iv) doses of MDL 27,088 or its prodrug, MDL 27,210. Although in both species iv-administered MDL 27,210 was extensively (> 99.9%) metabolized and excreted in the urine and feces as MDL 27,088, the disposition of MDL 27,088 appeared to be significantly influenced by its mode of administration. For example, the mean terminal half-life of MDL 27,088 in plasma was longer when MDL 27,088 was given as its prodrug (3.65 and 2.23 h in monkeys and dogs, respectively) than when it was administered directly (0.84 and 1.05 h in monkeys and dogs, respectively). The renal excretion of MDL 27,088 also increased (from 33 to 73% of the dose in monkeys and from 9 to 17% of the dose in dogs) when MDL 27,088 was administered directly versus when it was given as its prodrug. These and other results of this study suggest that the disposition of MDL 27,088 can be significantly altered by iv administration of its prodrug form. Such changes in disposition also suggest that iv administration of prodrug may influence the pharmacological activity of MDL 27,088.     

Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration

The pharmacokinetics (half-life time of absorption and elimination, total clearance, distribution volume etc.), effects on hemostasis (clotting times, blood cell counts) and renal excretion of hirudin were investigated on healthy volunteers after single subcutaneous (600, 800 or 1000 antithrombin units (AT-U)/kg; n = 3 per each dose) or intravenous (1000 AT-U/kg; n = 3) injections. Hirudin concentrations in citrated plasma and urine were determined by means of a radioimmunobioassay, whereby the inhibitor is detected by its thrombin binding capacity. Plasma profiles were adequately described by the Bateman equation (subcutaneous injection) and by an open two-compartment model (intravenous injection), respectively. Within 24 h about half of the applied hirudin dose was renally excreted in active form. The prolongation of clotting times (thrombin time, partial thromboplastin time (PTT), Quick) was dependent on the hirudin plasma level. The PTT proved to be the most reliable test for representation of the actual inhibitor plasma concentrations. Generally, the blood cell counts were unchanged by the hirudin administration. All test subjects tolerated the hirudin injection without visible or measurable side effects.     

雷公藤甲素在Beagle犬体内毒代动力学研究

目的：探索性研究雷公藤甲素在犬体内的毒代动力学特征,并观察其毒性反应,为雷公藤甲素毒性机制的深入研究提供研究数据.方法：25只Beagle犬随机分为5组,分别为灌胃给药A组（高剂量,0.1 mg/kg）、B组（中剂量,0.08 mg/kg）、C组（低剂量,0.05mg/kg）,静脉给药D组（0.08 mg/kg）和空白对照组E组,连续给药14d,于给药第1、7和14天采集血样或组织样本供毒代动力学研究及毒性检查（血常规、血生化、病理切片）;14 d给药过程中进行临床症状观察.结果：雷公藤甲素给药后第1天和第14天,静注和口服药代参数均有所变化,静注AUC0-从145.86增加到276.24 ng· h·mL-1,CL从548.45降到301.89mL·h^-1·kg^-1;口服高剂量 AUC0-∞从 151.54 增加到289.98 ng·h·mL^-1,Cmax从44.49增加到75.26 ng/mL;口服中剂量AUC0-∞从37.78增加到61.65 ng· h·mL^-1,Cmax从44.49增加到75.26 ng/mL;口服低剂量AUC0-∞从67.92增加到143.98 ng·h·mL^-1,Cmax从24.05增加到38.07 ng/mL.MRT、T1/2延长.毒性观察结果显示,毒性呈剂量和时间相关性,均出现不同程度的胃肠道反应,肝功能受损,白细胞降低等.结论：本文探索性研究了雷公藤甲素在犬体内的毒代动力学的性质,提示胃肠道和肝脏可能是两个主要的毒性靶器官,同时研究发现给药途径对雷公藤甲素的安全性有较大影响.     

Pharmacokinetics of ambenonium chloride in dogs after intravenous and oral administration

Plasma concentrations of ambenonium chloride (Mytélase) were studied, using a high pressure liquid chromatographic technique, in 11 dogs, after intravenous or oral administration of the drug. The results found suggest a complex multi-compartment storage with several periodical releases in general circulation.     

Hemodynamic effects of etacizine and lidocaine after intravenous administration in dogs

In acute experiments on anaesthetized dogs, the haemodynamic effect of etacizine (0.5 and 1.0 mg.kg-1 i.v.) and lidocaine (2.5 and 10 mg.kg-1 i.v.) were compared. Etacizine produced a decrease in heart rate and a temporary decrease in myocardial contractility. After the dose of 1 mg.kg-1 there occurred a temporary increase in peripheral vascular resistance. It did not affect aortal blood pressure, systolic and minute output volume of the heart. Lidocaine produced a decrease in heart rate, aortal blood pressure, systolic and minute output cardiac volume with a rapid return to the original values. Besides this negative effect it was possible to observe an increase in the minute output volume and peripheral vascular resistance with larger doses, which gives evidence of the central effect of the drug.     

Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine.

The purpose of this project was to characterize the dose-dependent pharmacokinetics of buprenorphine (BN) and norbuprenorphine (NBN), the primary metabolite, after intravenous administration of different doses of BN to rats. Adult male Sprague-Dawley rats were divided into six groups and received a single intravenous bolus dose of 0.1, 0.3, 1, 3, 10 or 30 mg/kg of BN. A separate study was performed where BN and NBN were simultaneously administered intravenously (1 mg/kg+1 mg/kg). Plasma samples were obtained by centrifugation of the blood and analyzed for BN and NBN using a sensitive and selective gas chromatographic-mass spectrometric (GC-MS) bio-analytical method. Noncompartmental and compartmental methods were used to perform pharmacokinetic data analysis. BN declined triexponentially with a dose-dependent increase in its volume of distribution, V(ss) (8.37-18.2 l/kg) and clearance CL (2.70-6.10 l/h per kg). The pharmacokinetics of NBN were linear and biexponential. Coadministration of BN and NBN resulted in a significant increase in the volume of distribution and clearance of BN. The present results suggest that the nonlinear disposition in the clearance and volume of distribution of BN can be attributed, in part, to the increasing concentration of the metabolite.     

Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients.

1. Plasma levels of 5-fluorouracil (5FU) have been determined in eleven cancer patients after 0.5 g and 1.0 g intravenous doses, and in one patient after paired 1.0 g oral and intravenous doses. 2. The plasma half-life after the 0.5 g intravenous dose was relatively constant, irrespective of the stage and spread of the disease. 3. Plasma kinetics of the drug were dose dependent. Doubling of the intravenous dose produced a 1.5-fold increase in plasma half life, a two-fold increase in initial plasma drug concentration, and a three-fold increase in area under the concentration/time curve. 4. In one patient receiving paired 1.0 g intravenous and oral doses nine weeks apart, an increase in the bioavailability of the drug coincided with a marked clinical regression in palpable intra-abdominal metastases. 5. The significance of measuring plasma drug kinetics and their relationship to drug efficacy and toxicity are discussed.     

Comparison of naltrexone and quaternary naltrexone after systemic and intracerebroventricular administration in pigeons

The behavioral effects of naltrexone and quaternary naltrexone were evaluated in two groups of pigeons. One group responded under a fixed-ratio schedule of food reinforcement and was trained to discriminate between 3.2 mg/kg morphine (i.m.) and saline. Drug-appropriate responding occurred in a dose-related manner to morphine, given intramuscularly and intraventricularly. When administered intraventricularly morphine was 50 times more potent as a discriminative stimulus and 50-100 times more potent at suppressing responding. Naltrexone, given intraventricularly and intramuscularly, attenuated the discriminative stimulus effects of morphine. Quaternary naltrexone was more potent at suppressing responding when administered intraventricularly but it failed to attenuate the discriminative stimulus effects of morphine. A second group of pigeons, responding under a variable-interval schedule of food reinforcement, was treated with 100.0 mg/kg/day of morphine. Naltrexone and quaternary naltrexone suppressed responding by both routes of administration. Naltrexone was approximately equipotent when given intramuscularly or intraventricularly, and the doses that suppressed responding were 50-500 times smaller than doses required to suppress responding in untreated pigeons. Although quaternary naltrexone was 1800 times more potent when given intraventricularly, the doses necessary to suppress responding by each route were the same as doses required in untreated pigeons. These results extend the conditions under which a quaternary derivative of naltrexone failed to display antagonist activity in the pigeon. The utility of this compound for characterizing central and peripheral mechanisms of action has not been established in different species and testing conditions and, therefore, appears to be appropriate only under conditions in which it is evaluated after systemic, as well as central, administration.     

人工合成胸腺素α1在猴体内静脉注射的药动学研究

目的：研究人工合成胸腺素α1（sTα1）在猴体内i.v.的血药浓度-时间曲线、药动学参数特点。方法：用竞争性ELISA法测定sTα1在猴体内i.v.后血清中的药物浓度,用DAS药动学统计软件进行血药浓度-时间曲线拟合及药动学参数计算。结果：猴i.v.sTα11.2mg/kg的药动学特征符合二室开放模型,呈一级动力学消除。结论：猴i.v.sTα1的药动学行为符合二室一级消除。     

Plasma profiles of lycopene after single oral and intravenous administrations in dogs

The objectives of this study were to identify the factors limiting the absorption of purified lycopene after oral administration, and to comparatively assess plasma data sets after single oral and intravenous administrations in dogs to define the conditions for performing an absolute bioavailability study. Solubility of purified lycopene (all-trans, 93.5%) was determined in media simulating the conditions in the fasted and in the fed upper gastrointestinal lumen. After evaluating the plasma levels achieved following single administrations of purified lycopene powder to fasted and fed dogs at escalating doses (75-750 mg), a crossover study was performed in four fed female mongrel dogs at two phases. In phase I, one soft gelatine capsule (10 mg lycopene) with 500 mL milk was administered orally. In phase II, 500 mL milk was administered orally and 250 mL 5% dextrose containing 5 mg lycopene in the form of a binary system with hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) was administered intravenously over 3.5 h. In-vitro and preliminary canine studies confirmed that, after oral administration of lycopene in solid form, arrival of lycopene into the systemic circulation was limited by lymphatic transport and, in addition, if the administered dose was higher than approximately 2 mg, by intralumenal solubility. During the first 50 h after single administrations to fed dogs, lycopene plasma levels were lower after intravenous than after oral administration. This could have been related to capacity limited elimination of lycopene and/or route-dependent disposition kinetics. Estimation of the amount of lycopene reaching the systemic circulation after oral and after intravenous administration requires separate estimations of total body clearance of lycopene.     

Pharmacokinetics of magnesium lithospermate B after intravenous administration in beagle dogs

AIM: To develop a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the phar-macokinetic study of magnesium lithospermate B (MLB), and study the pharmacokinetics of MLB after iv administration in beagle dogs. METHODS: Each beagle dog was iv administered MLB 3, 6, and 12 mg/kg random. The serum drug concentration was determined by specific liquid chromatography-tandem mass spectrometry (LC-MS/ MS) assays. The pharmacokinetic parameters were calculated by Drug and Statistics version 1.0 program. RESULTS: The calibration curve for MLB was linear over a range of 16-4096μg/L with coefficients of correlation >0.999. The intra- and inter-day precisions (CV) of analysis were <10 %, and accuracy ranged from 90 % to 113 %. After iv administration of MLB at the doses of 3, 6, and 12 mg/kg, the C0 values for MLB were estimated to be of 24, 47, and 107 mg/L, respectively. The AUC increased with the increasing doses for iv administration, and the mean AUC0-t values were 109.3, 247.9, and 5     

Clinical pharmacokinetics of ketoprofen after single intravenous administration as a bolus or infusion

The pharmacokinetics of ketoprofen were evaluated in 29 patients suffering from acute renal colic following a single intravenous administration as a bolus or short infusion (1.5 and 2 hours), and after a loading dose and a 24-hour infusion. Serum concentrations of ketoprofen were measured by high pressure liquid chromatography. The mean (+/- SD) values of clinical parameters were as follows: distribution half-life = 0.34 +/- 0.19 h; elimination half-life = 2.05 +/- 0.58 h; kel = 0.968 +/- 0.282 h-1; k21 = 0.943 +/- 0.425 h-1; k12 = 1.004 +/- 0.708 h-1; volume of central compartment = 5.58 +/- 1.67L; volume of tissue compartment = 5.14 +/- 2.12L; plasma clearance = 5.10 +/- 1.14L/h. These results concur with previously published data obtained after oral or intramuscular administration. According to clinical observations, administration of a ketoprofen bolus suppressed pain within 5 to 30 minutes; the administration of a loading dose and a 24-hour infusion is almost never followed by a recurrence of pain, and this regimen was proposed as the dosage schedule of ketoprofen to treat renal colic.