The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination

The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3-31.3 l), plasma clearance (249-2.88 ml/min), and renal clearance (151-177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54 +/- 6, 19 +/- 4, 6.5 +/- 0.7 and 5.5 +/- 0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3 +/- 0.4, 2.2 +/- 0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83 +/- 0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 +/- 226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 +/- 24 l). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92-94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0-1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.     

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.     

Disposition of HI-6 oxime in rats after intravenous and intramuscular administration

The pharmacokinetics of HI-6, a cholinesterase-reactivating oxime, were studied in rats, following intravenous or intramuscular administration. A two-compartment model was used to analyse the intravenous data and a one-compartment open model with first-order absorption was used for intramuscular data. Drug concentration had no influence on rate and extent of absorption of intramuscular injections, and bioavailability was 100%. Peak plasma concentrations of HI-6 occurred 15 min after intramuscular injection. No significant differences were found between mean values for half-life, plasma clearance, volume of distribution and area under the plasma concentration versus time curve for the two intramuscular doses and the intravenous dose used. Mean HI-6 plasma concentrations were 140.5 +/- 4.2 micrograms ml-1 3 min after 20 mg ml-1 i.v., with a mean elimination half-life of 65.2 +/- 21 min. Plasma clearance rate was 3.95 +/- 0.93 ml min-1 kg and the apparent volume of distribution was 0.38 +/- 0.17 litre kg-1. The oxime is rapidly distributed in and eliminated by rats when administered intravenously or intramuscularly.     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.     

Remoxipride: pharmacokinetics and effect on plasma prolactin.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four remoxipride administrations and independent of the given dose.     

Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered IIb/IIIa antagonist, in patients with acute coronary syndrome.

Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once- or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h; and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough excursions in active drug concentrations: trough concentrations were 21% +/- 6% of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were 54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose-adjusted steady-state active drug concentrations increased with increasing age and with decreasing renal function and body weight.     

Epinephrine absorption after different routes of administration in an animal model

BACKGROUND: The administration of epinephrine is the most important initial treatment in systemic anaphylaxis. PURPOSE: We wanted to determine the relationship between the route of epinephrine administration and the rate and extent of epinephrine absorption. METHODS: In a prospective, randomized, five-way crossover study in rabbits, we measured plasma epinephrine concentrations before, and at intervals up to 180 min after epinephrine administration by intramuscular or subcutaneous injection, or by inhalation, with intravenous epinephrine and intramuscular saline as the positive and negative controls, respectively. RESULTS: Maximum plasma epinephrine concentrations were higher, and occurred more rapidly, after intramuscular injection than after subcutaneous injection or inhalation, and were 7719+/-3943 (S.E.M.) pg/mL at 32.5+/-6.6 min, 2692+/-863 pg/mL at 111.7+/-30.8 min and 1196+/-369 pg/mL at 45. 8+/-19.2 min, respectively. Intravenous injection of epinephrine resulted in a plasma concentration of 3544+/-422 pg/mL at 5 min, and an elimination half-life (t(1/2)) of 11.0+/-2.5 min. In the saline control study, the endogenous epinephrine concentration peaked at 518+/-142 pg/mL. CONCLUSION: In this model, absorption of epinephrine was significantly faster after intramuscular injection than after subcutaneous injection or inhalation. The extent of absorption was satisfactory after both intramuscular and subcutaneous injections. Neither the rate nor the extent of absorption was satisfactory after administration by inhalation.     

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.     

Pharmacokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal subjects

The pharmacokinetics of bumetanide was studied in 12 normal subjects after 1-mg intravenous, intramuscular, oral solution, and tablet administrations in a random four-treatment crossover design. Plasma and urine concentrations of intact bumetanide were analyzed by a sensitive and specific RIA. The pharmacokinetics of bumetanide after intravenous administration was characterized by a biexponential equation, including an initial disposition phase (t 1/2, alpha = 5.1 min), followed by a slower elimination phase (t 1/2, beta = 44 min). Bumetanide pharmacokinetics after intramuscular and oral administration could be described by a biexponential equation with first-order absorption and elimination. Bumetanide is rapidly absorbed via the intramuscular and oral routes, with mean +/- SD maximum plasma concentrations of 38.2 +/- 9.8 (intramuscular), 34.0 +/- 10.6 (oral solution), and 30.9 +/- 14.6 ng/mL (tablet) achieved within 0.34 +/- 0.23, 0.76 +/- 0.27, and 1.8 +/- 1.2 h after dosing, respectively. The drug is rapidly eliminated from the body after intravenous, intramuscular, oral solution, and oral tablet administrations, with half-lives ranging from 24-86, 47-139, 27-71, and 26-99 min, respectively. Approximately 70% of a parenteral dose and 60% of an oral dose are excreted as intact drug in urine taken 0-24 h after administration. The extent of bioavailability of bumetanide from the tablet and oral solution dosage forms are equivalent, and the absolute bioavailability of the intramuscular and oral preparations are approximately 100 and 80%, respectively. This is consistent with the predicted limited extent of first-pass metabolism after complete absorption of an oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and bioavailability of dilevalol in normotensive volunteers

The bioavailability and pharmacokinetics of dilevalol following oral and intravenous administration were investigated in 12 healthy male volunteers. Dilevalol HCl was administered as a 200-mg oral tablet and a 50-mg intravenous infusion using a randomized cross-over design. Blood and urine samples were collected over 60 hours and analyzed for unchanged and total (unchanged plus Glusulase-released) dilevalol using a high performance liquid chromatography (HPLC) assay. After intravenous administration, total body clearance and volume of distribution of unchanged dilevalol were determined to be 23.2 mL/min/kg and 24.6 L/kg, respectively. After oral administration, a mean maximum concentration of 62 ng/mL was reached at an average peak time of 1.4 hours. Drug was eliminated with a half-life of 8.3 hours after oral administration and 12 hours after intravenous administration. Based on plasma levels and urinary excretion of total dilevalol, the drug was completely absorbed; however, due to first-pass metabolism, the absolute bioavailability of unchanged drug was 11 to 14%.     

Bioavailability and mammary excretion of bisphenol a in Sprague-Dawley rats.

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 +/- 1.3 min and 52.5 +/- 2.4 min, respectively. The systemic clearance (Cls) and the steady-state volume of distribution (Vss) averaged 107.9 +/- 28.7 m/min/kg and 5.6 +/- 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 14.7 +/- 10.9 ng/ml and 0.2 +/- 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 +/- 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 +/- 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.     

Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction

Tenecteplase is a site-specific engineered tissue plasminogen activator (t-PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose-ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t-PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt-PA as the accelerated 90-minute infusion regimen in this randomized, open-label study. Tenecteplase and r-tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half-life of 22 minutes and a mean terminal half-life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt-PA has a fourfold faster plasma clearance. Pharmacokinetic-pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r-tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt-PA, allowing dosing as an i.v. bolus injection. Weight-adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.     

Pharmacokinetics of sotalol enantiomers in humans.

The chiral beta-blocker, sotalol (STL), is marketed as a racemic mixture. Although both STL enantiomers have equal Class III antiarrhythmic activity, beta-blocking activity has been ascribed mainly to the R-enantiomer. The pharmacokinetics of STL enantiomers were studied in young (mean age 32 +/- 3 years), healthy male volunteers after oral administration of 160 mg. Subsequent plasma and urine samples were collected over 24 hours, and STL enantiomer concentrations were determined using a stereospecific high-performance liquid chromatography assay. There were no significant differences between pharmacokinetic parameters of enantiomers. The area under the time-concentration curves (mean +/- standard deviation [SD]) were 6.95 +/- 0.85 and 6.76 +/- 1.2 (mg/L)hour for S- and R-STL, respectively. Maximal plasma concentrations of S- and R-STL were 615 +/- 167 and 619 +/- 164 ng/mL, respectively, which were obtained on average, 3.13 +/- 0.60 hours after dosing. The mean residence time (mean +/- SD) was 13.2 +/- 1.2 and 12.9 +/- 1.8 hours for S- and R-STL, respectively. Respective renal clearance values for S- and R-STL were 8.98 +/- 1.5 and 9.46 +/- 2.3 L/hour, and were approximately 1.5 times greater than creatinine clearance. Renal clearance constituted approximately 76% of the oral clearance. Although stereoselective disposition of STL was absent after racemate administration, these results should not be extrapolated to patients with significantly altered physiology, or to the pharmacokinetics of S-STL after administration of pure-S-STL.     

Enzyme replacement in Fabry disease: pharmacokinetics and pharmacodynamics of agalsidase alpha in children and adolescents

This multicenter, open-label study evaluated pharmacokinetics, pharmacodynamics, and safety of agalsidase alpha in pediatric compared with adult patients with Fabry disease. The pharmacokinetic parameters of pediatric patients (19 boys, 5 girls, 6-18 years old; mean age, 11.8 years) were compared to those of adult male and female patients who participated in other clinical studies. All patients received agalsidase alpha at a dose of 0.2 mg/kg infused over 40 minutes every other week. Agalsidase alpha exhibited a biphasic serum elimination profile with a maximum serum concentration at the end of the 40-minute infusion; <1% of the maximum concentration was detected 8 hours after dosing. In children, serum clearance was 2.0 to 9.4 mL/min/kg and tended to decrease with increasing age. The average clearance in children, 3.7 +/- 1.5 mL/min/kg (mean +/- SD), was significantly greater than that measured in 33 adults (2.3 +/- 0.7 mL/min/kg, P < .0001). Mean terminal elimination half-life of agalsidase alpha was prolonged in week 25 compared with baseline (150 vs 66 minutes) in 8 of 19 male children. The magnitude of the reduction of plasma globotriaosylceremide was similar in all age groups and was independent of area under the curve and other pharmacokinetic parameters. Except for clearance in younger patients, agalsidase alpha appears to have comparable pharmacokinetic and pharmacodynamic profiles in pediatric and adult Fabry patients of both genders.     

Bioavailability and disposition of metoclopramide after single- and multiple-dose administration in diabetic patients with gastroparesis

The disposition of metoclopramide after acute and chronic administration was determined in four diabetic patients with gastroparesis who had a creatinine clearance of 70.8 +/- 10.7 mL/min (mean +/- SD). Single, 10-mg oral and intravenous doses were administered on days 1 and 2, respectively, followed by 10 mg orally every six hours for three weeks. A second, 10-mg intravenous bolus dose was administered on the last morning of chronic therapy. Metoclopramide concentrations were determined by high performance liquid chromatography. The elimination half-life, steady-state volume of distribution, and total body clearance after the initial intravenous dose were 3.9 +/- 1.2 hr, 2.7 +/- 0.3 L/kg, and 0.57 +/- 0.14 L/hr/kg, respectively. The initial bioavailability was 67.7 +/- 12.6%. After three weeks of chronic therapy, no significant differences in total body clearance (0.72 +/- 0.42 L/hr/kg) or bioavailability (77.5 +/- 16.8%) were observed. Thus the pharmacokinetics and bioavailability of metoclopramide were not altered during chronic therapy in these diabetic patients.     

Pharmacokinetics of intravenous bepridil in patients with coronary disease

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine ) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3 mg/kg and six patients received 4 mg/kg of bepridil infused over a period of 30 min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (+/- SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 +/- 820 ng/mL (3 mg/kg) and 2478 +/- 1426 ng/mL (4 mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7 h (range: 1.1-2.2 h) and 19.7 h (range: 8.0-61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9 h (range: 7.4-64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 +/- 0.215 L X kg-1 X h-1; Vd, 15.3 +/- 10.9 L/kg; and Vdss, 10.1 +/- 6.0 L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.     

Pharmacokinetics of sulpiride in humans after intravenous and intramuscular administrations.

The pharmacokinetics of sulpiride in plasma, red blood cells (RBC), and urine were investigated after administration of 100 mg by the iv route to 15 subjects and by the im route to 12 subjects. The concentrations of sulpiride in plasma, RBC, and urine were measured by HPLC. All the data were consistent with a two-compartment, open-body model. After iv administration, the mean +/- SD apparent elimination half-life of sulpiride was 6.47 +/- 1.00 h, and the mean +/- SD volume of distribution at steady state was 0.94 +/- 0.23 L/kg. Renal clearance (119.5 +/- 28.2 mL/min) was very close to total clearance (127.8 +/- 26.2 mL/min). In urine, the mean +/- SD recovery in form of the unchanged drug was 90.0 +/- 9.68% of the administered dose, and the excretion rate versus time showed an elimination half-life similar to that found in plasma. The values of all these parameters were very close to those obtained after im administration. The sulpiride partition coefficient between RBC and plasma did not show any significant change as a function of time and concentration, with a mean value +/- SD of 1.00 +/- 0.043, indicating that sulpiride is evenly distributed between RBC and plasma. The pharmacokinetic parameters determined from the plasma and the RBC data were similar.     

Pharmacokinetics of eltoprazine in the dog

Pharmacokinetics of eltoprazine in male and female beagle dogs was studied in two separate cross-over experiments after administration of different intravenous and oral doses. After intravenous administration of 0.5 mg.kg-1, the mean volume of distribution was 5.7 +/- 1.1 l.kg-1. Clearance was 25.5 +/- 1.4 ml.min-1.kg-1. About 25% of the doses was excreted in urine, resulting ina renal clearance of 6.1 +/- 1.4 ml.min-1.kg-1. The mean elimination half-life (t1/2) after intravenous dosing was about 2.6 h. After oral dosing the plasma peak levels (Cmax) were proportional with the dose. The mean time to reach Cmax (tmax) varied between 1.5 and 1.9 h, and t1/2 was about 2.4 h, which was not significantly different (p greater than 0.05) from the half-life obtained after intravenous dosing. Plasma pharmacokinetics after single and multiple dosing of 4 mg.kg-1 showed no difference. Absolute bioavailability was 67% +/- 20%.     

Pharmacokinetics of parenteral dezocine in rhesus monkeys and dogs

Pharmacokinetic parameters of the analgesic, dezocine, were determined after intravenous and intramuscular injection (1 mg/kg) to rhesus monkeys and dogs. In both species, the drug was rapidly distributed after intravenous administration and then eliminated with a mean half-life of 2.4 hr. Systemic clearance was 54.8 +/- 8.6(SD) and 65.8 +/- 14.0(SD) ml/min/kg in the rhesus monkey and dog, respectively. Glucuronidation was recognized as a major metabolic pathway in both species, and sulfate conjugation was indicated in the dog. Renal elimination of dezocine was minimal. Less than 4% of the dose was eliminated as unchanged dezocine in urine of rhesus monkeys and 1% of the dose in dog urine. After im administration, release from the injection site was rapid and no metabolism at the injection site was indicated. Multiple-dose experiments in dogs did not reveal accumulation. The acquisition of data was made possible by the development of a sensitive, specific assay, which depends on gas-liquid (electron capture) chromatography of a pentafluorobenzoylated derivative of dezocine.     

Clinical pharmacokinetics of bretylium

Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)