The pharmacokinetics of nalmefene, a new narcotic antagonist which has recently been shown to be effective in the treatment of a stereotypic behavior disorder (crib-biting) in the horse, has been evaluated. Following rapid i.v. injection of a pharmacologically effective dose of 0.4 mg/kg of nalmefene HCl to two crib-biting horses, the plasma concentration - time profile of intact nalmefene declined rapidly in a biexponential manner with a terminal elimination of half-life (t1/2) of approximately 50 min in both animals. Total plasma clearance (CL) and the volume of distribution at steady-state (V(ss)) were 2.8 L/hr/kg and 2.5 L/kg, respectively, indicating high clearance and extensive distribution of the drug. Following i.m. injection of 1 mg/kg of the drug to three other horses, nalmefene had an "apparent" t1/2 of 3 to 5 hr which suggests some form of depot effect or altered disposition occurred via this route of administration. After oral administration of 2 mg/kg of nalmefene, no intact drug could be detected in plasma. However, high plasma concentrations of nalmefene glucuronide appeared rapidly and were detectable for up to 16 hr following administration. The latter observation indicates that nalmefene has poor oral bioavailability in the horse as a result of extensive "first-pass" metabolism and must be administered parenterally for effective control of stereotypic behavior.

The pharmacokinetics of a new inotropic catecholamine, N-[2-(3,4-dihydroxyphenyl)-ethyl]-1-methyl-3-(3-carbomylphenyl)-pr opylamine HCL (KM-13), was studied following i.v. injection of 50 and 100 micrograms/kg doses to dogs. KM-13 was extracted from plasma using Bond-Elut CN columns and quantitated by HPLC with electro-chemical detection. The plasma concentration--time profile of KM-13 following an i.v. bolus was best fitted with a bi-exponential equation and the terminal elimination phase had a half life of about 20 min. The analytical method, with a limit of sensitivity of 2 ng/ml, would appear to have general applicability in studying the pharmacokinetics of synthetic catecholamines.

The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model-independent pharmacokinetic analysis of the plasma concentration-time data showed that nalmefene was rapidly absorbed and had an elimination half-life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a beta-glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50-mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven-day administration period.(ABSTRACT TRUNCATED AT 250 WORDS)

Using a newly developed iontophoretic delivery device, a novel inotropic catecholamine, pharmacologically similar to dobutamine, has been successfully administered to dogs by noninvasive transdermal infusion for periods of up to 1.5h. The technique was compared with intravenous infusion and shown to be capable of achieving the same degree of cardiac contractility and steady-state plasma concentrations of the inotrope. There was also a good linear relationship between the applied current and the resulting steady-state plasma concentrations of the inotrope. Approximately 2mA of applied current during transdermal iontophoresis produced a response equivalent to an intravenous infusion of 1 μg/kg/min of the drug.

In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.

A simple high performance-liquid chromatographic procedure employing electrochemical detection (LC-EC) has been developed for the quantitation of the cardiotonic agent dobutamine and a new pharmacologically active congener. The drugs were extracted from plasma by adsorption on to alumina, eluted from the adsorbent with dilute perchloric acid and the eluate subjected to LC-EC. The method had a limit of sensitivity of 1 ng/ml of plasma for each drug. The applicability of the LC-EC procedure was demonstrated by determining steady-state plasma concentration profiles of dobutamine and its congener in man and dog, respectively, following i.v. infusion of the drugs.

A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration.

A high performance-liquid chromatographic procedure employing electrochemical detection (LCEC) has been developed for the quantitation of a new narcotic antagonist, nalmefene, in human plasma. Following extraction of the plasma at pH9, the extract was chromatographed on a reverse-phase C18 column using naltrexone as an internal standard. An electrochemical detector equipped with a glassy carbon electrode monitored the elution of nalmefene and the internal standard. The method had a limit of sensitivity of 3 ng/ml of nalmefene using a 1 ml sample of plasma and the calibration curve was linear over a range of 3-200 ng/ml. The intra- and inter-assay coefficients of variation did not exceed 6 and 12% respectively over the entire range of the calibration curve. The LCEC method has been used to quantitate the plasma concentrations of nalmefene in man following oral administration of 64 mg of the drug. In one subject, a peak plasma concentration of 58 ng/ml occurred 2 hr after drug administration and declined to 5 ng/ml after 24 hr.