Simultaneous determination of 2,4-D and MCPA in canine plasma and urine by HPLC with fluorescence detection using 9-anthryldiazomethane (ADAM).

A method for the simultaneous determination of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in canine plasma and urine has been developed. This method used derivatization of extracted samples with 9-anthrylmethane (ADAM) for analysis by reversed-phase high-performance liquid chromatography with fluorescence detection. Precision and accuracy were within the accepted limits of 15% and 85-115%, respectively, for both analytes in plasma and urine. Calibration curves for 2,4-D and MCPA in plasma were linear (r2 > 0.99) between 0.50 and 5.0 mg/L and 5.0 and 100 mg/L. Calibration curves for 2,4-D and MCPA in urine were linear (r2 > 0.99) between 5.0 and 70.0 mg 2,4-D/L and 10.0 and 70.0 mg MCPA/L. The lower limit of detection was 62.5 ng/mL for both 2,4-D and MCPA.

Detection and identification of flunixin after multiple intravenous and intramuscular doses to horses.

The objectives of the study were to compare various methods to determine flunixin in test samples collected periodically from horses after intramuscular (IM) and intravenous (IV) dosing at the maximum recommended dosage and to document detection times for this drug in test samples. Flunixin, a nonsteroidal anti-inflammatory drug approved for use in horses, was administered to eight mares in five consecutive daily doses of 1.1 mg per kilogram of body weight by the IM or IV route. Flunixin was detected in urine samples collected at various times after drug administration by flunixin enzyme-linked immunosorbent assay (ELISA), thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and gas chromatographic-mass spectrometric (GC-MS) methods. Detection time was defined as the time period over which flunixin was detected and was dependent on the method used. The shortest detection times were 24 to 48 h and were observed when the TLC method was used. On the other hand, detection times were as long as 15 days when HPLC, GC-MS, and flunixin ELISA methods were used. The use of these more sensitive tests to monitor official samples collected from racehorses could result in positive tests for flunixin when it is exerting no detectable clinical effects because it produces clinical effects lasting only 24-36 h in horses.

Pharmacokinetics of multiple-dose administration of eltenac in horses.

OBJECTIVE: To compare pharmacokinetics of eltenac after first and last IV administrations (0.5 mg/kg), using a multiple dosing schedule. ANIMALS: 6 adult mares. PROCEDURE: Eltenac (50 mg/ml) was administered IV at a dosage of 0.5 mg/kg of body weight every 24 hours for days 0 through 4. On days 0 and 4, blood samples were collected before, then periodically for 8 hours after eltanac administration. Concentration of eltenac in plasma samples was determined by use of high-performance liquid chromatography. RESULTS: On day 0, median area under the plasma eltenac concentration versus time curve (AUC) was 6.77 microg.h/ml (range, 5.61 to 8.08 microg.h/ml), median plasma clearance was 1.23 ml/min/kg (range, 1.03 to 1.40 ml/min/kg), and median steady-state volume of distribution was 191 ml/kg (range, 178 to 218 ml/kg). Median terminal half-life of eltenac was 2.36 hours (range, 2.30 to 2.98 hours). On day 4, median eltenac AUC was 6.70 microg.h/ml (range, 5.21 to 7.44 microg.h/ml), median plasma clearance was 1.23 ml/min/kg (range, 1.12 to 1.53 ml/min/kg), and median steady-state volume of distribution was 193 ml/kg (range, 172 to 205 ml/kg). Median terminal half-life of eltenac was 2.40 hours (range, 2.11 to 3.25 hours). Protein binding of eltenac, determined by ultrafiltration, was > 99% at a total plasma concentration of 36 microg/ml. CONCLUSION: Pharmacokinetic variables determined for each horse were not different between days 0 and 4. CLINICAL RELEVANCE: Under conditions of this study, there was no clinically relevant accumulation of eltenac in equine plasma or alteration of pharmacokinetic variables after multiple IV dosing of 0.5 mg/kg of eltenac.

Pharmacokinetics of intravenous and intragastric cimetidine in horses. I. Effects of intravenous cimetidine on pharmacokinetics of intravenous phenylbutazone.

Cimetidine was administered intravenously and by the intragastric route to six mares at a dose of 4.0 mg/kg of body weight (bw). Specific and sensitive high performance liquid chromatographic methods for the determination of cimetidine in horse plasma and urine and cimetidine sulfoxide in urine are described. Plasma cimetidine concentration vs. time data were analysed by non-linear least squares regression analysis to determine pharmacokinetic parameter estimates. The median (range) plasma clearance (Cl) was 8.20 (4.96-10.2) mL/min.kg of body weight, that of the steady-state volume of distribution (Vdss) was 0.771 (0.521-1.15) L/kg bw, and that of the terminal elimination half-life (t1/2 beta) was 92.4 (70.6-125) minutes. The median (range) renal clearance of cimetidine was 4.08 (2.19-6.23) mL/min.kg bw or 55.4 (36.3-81.8)% of the corresponding plasma clearance. Cimetidine sulfoxide was excreted in urine and its urinary excretion through 8 h accounted for 12.0 (9.8-16.6)% of the plasma clearance of cimetidine. The median (range) extent of intragastric bioavailability was 14.4 (6.82-21.8)% and the maximum plasma concentration after intragastric administration was 0.31 (0.24-0.50) microgram/mL. Intravenous cimetidine had no effect on the disposition of intravenous phenylbutazone or its metabolites except that the maximum plasma concentration of gamma-hydroxyphenylbutazone was less after cimetidine treatment.

Pharmacokinetics of intravenous and oral prethcamide in horses.

The respiratory stimulant prethcamide is a mixture of equal parts of crotethamide and cropropamide. A specific and sensitive gas chromatographic method for the determination of crotethamide and cropropamide in horse plasma and urine is described. Both components of prethcamide were extracted from plasma and urine into dichloromethane. The extracts were analyzed by capillary gas chromatography with thermionic detection in the nitrogen-specific detection mode. The lower limits of quantitation were 4.0 ng ml-1 of plasma and 10.0 ng ml-1 of urine. Calibration curves were linear from 2.0-100 ng ml-1 of plasma for both components. Pharmacokinetic parameters for crotethamide and cropropamide after intravenous and oral dosing were estimated by analysis of plasma concentration versus time data. The total plasma clearance of cropropamide was greater than that of crotethamide and both values were greater than 5 ml min-1 kg-1. Renal clearance values of the two drugs were comparable and were much less than estimates of filtration clearance values in horses, indicating extensive re-absorption of both components from the renal tubules. Both compounds were metabolized by N-demethylation of the [(dimethylamino)-carbonyl]-propyl moiety and these metabolites were excreted in urine. The method was demonstrated to be suitable for detecting illicit administration of prethcamide to competition horses.

Laboratory Culture of the Sepiolid Squid Euprymna scolopes: A Model System for Bacteria-Animal Symbiosis.

The small Hawaiian sepiolid Euprymna scolopes, with its symbiotic luminous bacterium Vibrio fischeri, was cultured through one complete life cycle in 4 months. Paralarval squid hatchlings were actively planktonic for the first 20-30 days, after which they settled and assumed the typical adult mode of nocturnal activity and diurnal quiescence. Squids were aggressive predators that preferred actively swimming prey up to 2-4 times their size; the only diet that yielded good survival and rapid growth for paralarvae was large adult mysids. Survival to settlement was 73% on this diet, whereas it was 0%-17% on controls and three other diets. Paralarvae initially lacked both detectable luminescence and V. fischeri cells in their incipient light organs; all remaining stages produced luminescence, and their light organs were colonized by apparently pure cultures of > 105 V. fischeri typical of E. scolopes symbiont strains. Survival from settlement to sexual maturity was 76%. Mating and egg laying commenced at 2 months, yet attempts to culture the next laboratory generation of hatchlings were not as successful. The results indicate that the host organism of this symbiosis can soon be cultured with consistency through its brief life cycle, thus opening new avenues of research into developmental aspects of this symbiosis.

Persistence of ivermectin in plasma and faeces following treatment of cows with ivermectin sustained-release, pour-on or injectable formulations.

Sixteen young dairy cows were randomly allocated to 4 groups of 4 animals each: Group 1 cows were each given a single Ivomec SR Bolus; Group 2 cows were treated with the Ivomec Pour-on formulation; Group 3 cows were injected with the Ivomec Subcutaneous Injection; Group 4 cows were untreated controls. Blood and faecal samples were collected from all cows on the day before treatment and on days 1, 2, 3, 7, 14, 21, 28, 35, 42 and 49 after treatment for HPLC determination of plasma and faecal ivermectin concentrations. Group 1 (SR Bolus) cows had mean (+/- S.D.) plasma ivermectin concentrations ranging from 5.6 +/- 1.8 micrograms l-1 (p.p.b.) at 14 days to 11.0 +/- 4.7 micrograms l-1 at 49 days. Faecal ivermectin concentrations were little changed from 4.0 +/- 2.0 micrograms g-1 (p.p.m.) dry wt (dry weight) [0.5 +/- 0.2 microgram g-1 wet wt (wet weight)] at 14 days to 3.0 +/- 2.0 micrograms g-1 dry wt (0.5 +/- 0.4 microgram g-1 wet wt) at 49 days. Group 2 (Pour-on) cows showed a rapid rise in plasma concentrations to 32.9 +/- 15.7 micrograms l-1 2 days after treatment, followed by a gradual decline to 1.3 +/- 0.07 micrograms l-1 at 28 days. Faecal ivermectin concentrations rose sharply to 18.5 +/- 7.4 micrograms g-1 dry wt (2.8 +/- 1.2 micrograms g-1 wet wt) 2 days after treatment, then fell to 0.04 +/- 0.004 microgram g-1 dry wt (0.006 +/- 0.0004 microgram g-1 wet wt) at 28 days. Group 3 (Injection) cows also showed a rapid rise to an early plasma peak of 46.1 +/- 22.7 micrograms l-1 3 days after treatment, followed by a gradual decline to 1.3 micrograms l-1 at 35 days. Faecal ivermectin concentrations rose to 1.2 +/- 0.34 micrograms g-1 dry wt (0.2 +/- 0.05 microgram g-1 wet wt) at 3 days, declining to 0.08 +/- 0.0001 microgram g-1 dry wt (0.01 +/- 0.0008 microgram g-1 wet wt) at 28 days. No ivermectin was detected in the plasma or faeces of Group 4 (Control) cows. Concentrations of ivermectin potentially toxic to dung-breeding or dung-feeding invertebrates were excreted for the duration of the study in dung of cows treated with the SR Bolus and for 28 days in the dung of cows treated with the Pour-on or injectable formulations.

Pharmacokinetics of ketoprofen after multiple intravenous doses to mares.

The pharmacokinetics and urinary excretion of ketoprofen in six healthy mares after the first and last of five daily intravenous doses of 2.2 mg of ketoprofen per kg body weight were investigated using a high-performance liquid chromatographic (HPLC) method for determining plasma and urinary ketoprofen concentrations. Plasma ketoprofen concentrations declined triexponentially after each dose with no significant differences in plasma concentrations or pharmacokinetic parameter values between the first and last doses. The harmonic mean of the terminal elimination half-life of ketoprofen after the first and last dose was 98.2 and 78.0 min, respectively. The median values of the total plasma clearance and the renal clearance after the first dose were 4.81 and 1.93 mL/min/kg, respectively. Total plasma clearance was attributed to renal excretion of ketoprofen and metabolism of ketoprofen to a base-labile conjugate which was also excreted in the urine. Renal clearance of ketoprofen was attributed to renal tubular secretion since renal clearance was greater than filtration clearance. Urinary recovery of ketoprofen during the first 420 min after the first dose accounted for 26.4% of the dose as unconjugated ketoprofen and 29.8% of the dose as a base-labile conjugate of ketoprofen. Total urinary recovery of ketoprofen as unchanged ketoprofen and from base-labile conjugate represented 56.2% of the dose. Plasma protein binding of ketoprofen was extensive; the mean plasma protein binding of ketoprofen was 92.8% (SD 3.0%) at 500 ng/mL and 91.6% (SD 0.60%) at 10.0 micrograms/mL.

Pharmacokinetics of florfenicol following intravenous and intramuscular doses to cattle.

The disposition of florfenicol after single intravenous and intramuscular doses of 20 mg of florfenicol/kg of body weight (b.w.) to feeder calves was investigated. Serum florfenicol concentrations were determined by a sensitive high performance liquid chromatographic method with a limit of quantitation of 0.025 microgram/ml. The extent of serum protein binding of florfenicol was only 13.2% at a serum florfenicol concentration of 3.0 micrograms/ml. Serum concentration-time data after intravenous administration were best described by a triexponential equation. Total body clearance and steady state volume of distribution were 3.75 ml/min/kg b.w. and 761 ml/kg b.w., respectively. The terminal half-life after intravenous administration was 159 min. The absolute systemic availability after intramuscular administration was 78.5% (range: 59.3-106%) and the harmonic mean of the terminal half-life was 1098 minutes, indicating slow release of the florfenicol from the formulation at the intramuscular injection site.

Pharmacokinetics of and serum thromboxane suppression by flunixin meglumine in healthy foals during the first month of life.

Age and species reportedly affect the pharmacokinetic variables of nonsteroidal anti-inflammatory drugs. We determined the effect of age on flunixin pharmacokinetic variables in foals during the first month of life. We also estimated the physiologic activity of the drug in neonatal foals by determining the effect of flunixin on thromboxane production during clotting of blood taken from the foals. Flunixin disposition and clearance were determined after IV administration of 1.1 mg of drug/kg of body weight to 5 healthy foals when they were 24 to 28 hours, 10 to 11 days, and 27 to 28 days old. The area under the curve (2,471 micrograms.min/ml), mean residence time (477 minutes), and zero-time intercept of the elimination phase (4,853 ng/ml) were significantly (P = 0.05) greater, the elimination half-life (339 minutes) and slope of the elimination phase (0.002 L/min) were significantly (P = 0.05) longer, and total body clearance (0.482 ml/min/kg) and zero-time intercept for the distribution phase (2,092 ng/ml) were significantly (P = 0.05) lower at 24 to 28 hours. At each age, a biexponential equation was best fitted to the plasma flunixin concentration from each foal. Thromboxane B2 production during clotting of blood was significantly (P = 0.05) suppressed for 12 hours after flunixin meglumine administration at all ages. Therefore, it appears that although age does alter the disposition and elimination of flunixin in neonatal foals, this effect may be of little consequence because the drug's physiologic activity in foals appears similar to that in mature horses.

Effects of concurrent administration of phenylbutazone and flunixin meglumine on pharmacokinetic variables and in vitro generation of thromboxane B2 in mares.

Flunixin meglumine and phenylbutazone are nonsteroidal anti-inflammatory drugs commonly used for the management of colic, endotoxemia, and musculoskeletal disorders in equids. Although it is not usually recommended, there appears to be an increasing trend to use nonsteroid anti-inflammatory drugs in combination to enhance or prolong their effects. Therefore, we studied the effect of concurrent administration of flunixin (1.1 mg/kg of body weight, IV) as flunixin meglumine and phenylbutazone (2.2 mg/kg, IV) on the pharmacokinetics of each drug and on in vitro thromboxane B2 production. Pharmacokinetic variables calculated for each drug when given alone and in combination were similar to those reported. Serum thromboxane B2 production was significantly (P = 0.05) suppressed for 12, 8, and 24 hours after administration of flunixin, phenylbutazone, and the drugs in combination, respectively. These results indicate that although concurrent administration of these drugs at the aforementioned dosages does not alter either drug disposition or clearance, it prolongs their pharmacologic effect.

The pharmacology and pharmacokinetics of high-dose methocarbamol in horses.

The haemodynamic, respiratory and behavioural effects and pharmacokinetics of methocarbamol were studied in eight healthy, adult horses after intravenous (i.v.) and oral administration of large dosages. Heart rate, cardiac output, mean pulmonary arterial blood pressure, systolic, diastolic and mean aortic blood pressure, respiratory rate and arterial blood gases did not change after either i.v. (30 mg/kg bodyweight [bwt]) or oral (50 and 100 mg/kg bwt) dosages of methocarbamol. Mild to moderate depression was observed in five of eight horses administered i.v. methocarbamol, and in all horses administered oral methocarbamol. Plasma methocarbamol concentration declined very rapidly during the initial or rapid disposition phase after i.v. administration; the terminal elimination half-life ranged from 59 to 90 mins. Peak plasma methocarbamol concentrations following oral administration occurred within 15 to 45 mins and oral bioavailability ranged from 50.7 to 124 percent.

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.

Reduction of the ventricular arrhythmogenic dose of epinephrine by ketamine administration in halothane-anesthetized cats.

The effect of ketamine administration on the ventricular arrhythmogenic dose of epinephrine (VADE) was studied in 4 halothane-anesthetized cats. Each cat was anesthetized 4 times, 1 week apart, with halothane (end-tidal concentration, 1.5%) and with halothane (end-tidal concentration, 1.5%) combined with ketamine infusion (50, 100, and 200 micrograms/kg of body weight/min). Epinephrine was infused in progressively increasing doses. The VADE (micrograms/kg) was calculated as the product of infusion rate of epinephrine and time of infusion necessary to induce 4 or more ventricular premature depolarizations within 15 s. The mean (+/- SD) VADE during halothane anesthesia was 1.1 (+/- 0.30) micrograms/kg. Ketamine infusion significantly (P less than 0.01) lowered the VADE independently of dose. The dose of epinephrine (micrograms/kg) that induced an ECG change in P-wave configuration was calculated similarly. Less epinephrine was necessary to induce a change in P-wave configuration than was necessary to induce 4 or more ventricular premature depolarizations within 15 s. Blood samples were collected after 4 hours of ketamine infusion and again immediately after determination of the VADE for analysis of plasma ketamine and norketamine concentrations by use of gas chromatography. Plasma ketamine and norketamine concentrations after a 4-hour infusion and immediately after determination of the VADE were similar for any given ketamine infusion rate, indicating that steady-state plasma concentrations had been reached for each infusion rate. Blood pressure and heart rate were measured immediately before (base line) and immediately after infusion of the VADE. Ketamine infusion significantly (P less than 005) lowered base-line blood pressure, but not heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares.

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.

Pharmacologic and pharmacokinetic properties of methocarbamol in the horse.

The hemodynamic, respiratory, and behavioral effects, as well as the pharmacokinetic properties of methocarbamol, were determined in horses. Heart rate, cardiac output, arterial and venous blood pressures, respiratory rate, and arterial blood gases did not change after IV methocarbamol (4.4, 8.8, 17.6 mg/kg) administration. There were no signs of behavior modification or ataxia observed. Analysis of plasma concentration time data indicated that the disposition of methocarbamol may be dose-dependent. Clearance and steady-state volume of distribution decreased as the dose increased. Plasma concentrations of guaifenesin, a metabolite of methocarbamol, were never greater than 0.5% of the plasma concentration of methocarbamol.

Pharmacokinetic quantitation of naltrexone controlled release from a copolymer delivery system.

Naltrexone release rates from a controlled release delivery system have been quantitated over a time period greater than one month in the monkey. The method requires calibration of the pharmacokinetic parameters of each monkey utilizing an intravenous bolus dose and assay of unchanged naltrexone levels in plasma as a function of time after dosing. Also required are periodic plasma levels of unchanged naltrexone obtained subsequent to administration of the delivery system. Release rates are then calculated as well as the total amount released. Application of the methodology to a biodegradable copolymer naltrexone delivery system in three monkeys showed an initial release rate of 3-8% of the dose per day over the first 3-5 days followed by a slow, rather constant release rate of 1-3% per day from day 5 to the time of the last measurable plasma sample (36-43 days). Comparison of alternative calculation methods using both experimental and simulated plasma naltrexone data verified the accuracy of the release rate calculations. The sum of the calculated total amount of naltrexone released plus the assayed amount remaining in the delivery system after removal from the animal accounted for 91-94% of the administered dose in the two monkeys in which complete data were obtained.

An electron-capture gas chromatographic assay for naltrexone in biological fluids.

The electron-capture gas chromatography assay for naltrexone is an adaptation of the method published originally by Sams and Malspeis (1). The current methodology, described in detail, consists of an extraction procedure, derivatization to form an electron-capturing triester, and gas chromatography using an OV-17 column. Extraction efficiencies indicate that either benzene or 0.25% butanol in cyclohexane used as the organic phase yields maximal extraction of naltrexone and minimal extraction of most naltrexone metabolites. Methylene chloride, on the other hand, yields an optimal combination of clean chromatograms and high extraction efficiencies for both naltrexone and its metabolites. Derivatization with either heptafluorobutyric anhydride or pentafluoropropionic anhydride together with a basic catalyst yields a triester derivative. Use of an OV-17 chromatographic column with electron-capture detection permits assay of naltrexone specifically with respect to known metabolites. One minor metabolite, 2-hydroxy-3-O-methyl-beta-naltrexol could interfere with naltrexone quantitation if present in sufficient quantities. This interference could readily be detected if it were to occur. Data on the reproducibility of this assay procedure indicate that it is sensitive to a concentration of 0.25 ng/ml plasma.

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.