Disposition and metabolism of carbovir in mice dosed intravenously or orally

To determine the disposition of carbovir and [3H]carbovir in mice, HPLC and thin-layer chromatographic assays were developed and mice were dosed iv and by gavage. Carbovir had no lethal effect at iv doses up to 500 mg/kg and was stable for 24 hr in mouse plasma at temperatures ranging from 0-37 degrees C. Binding to plasma proteins was minimal. Following an iv dose of 500 mg/kg of carbovir or [3H] carbovir, elimination phases with half-lives of 26-37 min (alpha) and 206-330 min (beta) were observed for plasma. For mice dosed with 27 mg/kg of [3H]carbovir, however, only a single phase with a half-life of 17 min was noted. Of several tissues examined, kidney contained the highest concentration of radioactivity. For the high dose, 19.0 +/- 2.6% was excreted in the urine in 24 hr as unchanged carbovir and 42.2 +/- 2.4% as metabolites; for the low dose, 54.5 +/- 6.1% was excreted as carbovir and 26.5 +/- 5.0% as metabolites. When mice were dosed orally with 500 mg/kg, plasma concentrations of carbovir were low. The initial plasma half-life for carbovir was 69 min; the terminal half-life was 822 min. Urinary excretion of unchanged carbovir was 21.3 +/- 7.1%. These results indicate that clearance of high doses of carbovir is limited and that its absorption is poor after oral dosing.     

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

Drug treatment poses a therapeutic challenge in cystic fibrosis (CF) because the disposition of a number of drugs is altered in CF. Enhanced clearance of acetaminophen (APAP) and indocyanine green (ICG) have previously been reported in CF patients. The objective of the current study was to investigate if the CF-knockout mouse model (cftr^m1UNC) shows altered pharmacokinetics similar to those seen in CF patients using the 2 model compounds APAP and ICG. Clearance (CL/F) of APAP and renal (CL_R) and formation (CL_f) clearance of acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were determined in CF-knockout mice following administration of APAP (50 mg/kg, intraperitoneal). CL_R of AS was 19.5 and 12.9 (mL/min per kg) and CL_f of AS was 10.4 and 6.7 mL/min per kg for homozygous and heterozygous males, respectively, which was significantly different between groups. CL_R of AG was 6.3 and 4.8 mL/min per kg and CL_f of AG was 9.6 and 8.9 mL/min per kg for homozygous and heterozygous males, respectively, although not reaching statistical significance. No significant differences were noted in either Cl_R or CL_f of AG and AS in female CF mice. Plasma concentrations of ICG (10 mg/kg, intravenous) were determined over 0 to 15 minutes. Homozygous females showed a higher apparent volume of distribution (96 mL/kg) relative to heterozygous females (72 mL/kg). Similar to CF patients, a trend toward a lower C_max was noted in homozygous male and female mice. However, contrary to human data, no significant differences in CL of ICG were noted. These results suggest that the CF-knockout mice have potential as a model for studying altered drug disposition in CF patients.     

Quinidine single dose pharmacokinetics and pharmacodynamics are unaltered by omeprazole

Omeprazole has been shown in previous studies to inhibit the hepatic metabolism of selected drugs. Quinidine is an antiarrhythmic and antimalarial agent with a low therapeutic index. We therefore examined the effect of 40 mg omeprazole daily for one week or placebo on the pharmacokinetics and pharmacodynamics of a single 400 mg dose of quinidine in 8 healthy volunteers in a double-blind crossover study. During placebo and omeprazole treatment, there was no significant difference in area under the time-plasma quinidine concentration curve, (17.0 +/- 4.83 micrograms.h/ml, 18.6 +/- 4.43 micrograms.h/ml, respectively; P greater than 0.2) or renal clearance of quinidine (56.2 +/- 26.0 ml/min, 55.6 +/- 12.7 ml/min, respectively; P greater than 0.5). Quinidine unbound fraction in plasma (0.170 +/- 0.041 vs. 0.166 +/- 0.041 in the presence of omeprazole; P greater than 0.5) was not altered by omeprazole. Peak plasma quinidine concentration and the time this occurred did not differ. Omeprazole also had no effect on these parameters for the metabolite 3-hydroxyquinidine. There was no significant difference in the change in the corrected Q-T interval on the electrocardiogram due to quinidine (mean area under the time versus delta Q-Tc curve = 351 +/- 192 ms.h, placebo; 414 +/- 303 ms.h, omeprazole) showing that quinidine pharmacodynamics were unaltered by omeprazole. We conclude that omeprazole does not affect the pharmacokinetics of quinidine.     

Effect of Pregnancy on Nitrofurantoin Disposition in Mice

We investigated the effect of pregnancy on nitrofurantoin (NFT) disposition in wild-type and Bcrp1^?/? mice. Pregnant and non-pregnant mice were administered NFT intravenously (5 mg/kg) or orally (10 mg/kg). Blood samples were collected at various times (5–60 min) after drug administration, plasma NFT concentrations determined by HPLC/UV, and pharmacokinetic parameters estimated. Dose-normalized area under the plasma concentration–time curve (AUC), terminal plasma half-life (T_1/2), total plasma clearance (CL), and steady-state volume of distribution (V_ss) of intravenous NFT in wild-type or Bcrp1^?/? mice were not altered by pregnancy. After oral administration, pregnancy did not affect dose-normalized AUC of NFT in wild-type mice; however, dose-normalized AUC in Bcrp1^?/? mice was decreased by approximately 70% by pregnancy. In conclusion, since Bcrp1 plays a minor role in the systemic clearance of NFT in female mice, pregnancy did not affect disposition of intravenous NFT despite the fact that Bcrp1 expression in the liver and kidney of mice is significantly induced by pregnancy. On the other hand, pregnancy may affect expression and activity of certain intestinal efflux transporters and/or metabolic enzymes in Bcrp1^?/? mice, resulting in a drastic decrease in the systemic exposure of oral NFT in pregnant Bcrp1^?/? mice. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4306–4315, 2009     

The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates

Summary The pharmacokinetics and metabolism of mepivacaine has been studied in premature neonates dosed subcutaneously and in healthy adults dosed intravenously. The pharmacokinetics of mepivacaine in four neonates (N) was compared with that in six adults (A). Newborns had a significantly longer terminal phase half-life than adults (N mean 8.69 h; A mean 3.17 h). Total plasma clearance normalized on body weight was significantly smaller in neonates (mean 2.34 ml/min/kg) than in adults (mean 5.47 ml/min/kg), as was the hepatic blood clearance (N mean 1.37 ml/min/kg; A mean 5.10 ml/min/kg). The renal plasma clearance, however, was significantly greater in neonates (mean 0.76 ml/min/kg) than adults (mean 0.20 ml/min/kg). There was an average six-fold increase in the fraction of the dose excreted unchanged in newborns (mean 43.3%) compared to adults (mean 7.1%) with acidified urine (pH 5.5–6.0). There was significantly more of the mono-N-demethylated metabolite of mepivacaine excreted by newborns (mean 11.4%) than by adults (mean 2.2%), but their capacity to carry out aromatic hydroxylation of mepivacaine was negligible. These results for mepivacaine were compared with those previously reported for lignocaine in premature infants. The immaturity of hepatic function appears to have diminished more profoundly the ability of premature infants to metabolize mepivacaine than lignocaine. These findings are discussed in terms of perfusion theory of hepatic drug elimination.     

Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat

The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Influence of fluconazole on the pharmacokinetics of omeprazole was evaluated by single oral administration of omeprazole capsule 20 mg (control group), or single oral administration of fluconazole capsule, 100 mg, and omeprazole, 20 mg, after 4 days of daily oral administration of fluconazole, 100 mg (treated group), to 18 healthy male volunteers. Omeprazole is extensively metabolized in the liver through 5-hydroxylation and sulfoxidation reactions catalyzed predominantly by CYP2C19 and CYP3A4, respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. In treated group, the area under the plasma concentration-time curve of omeprazole from time zero to time infinity (AUC) was significantly greater (3090 vs 491 ng h/ml), terminal half-life of omeprazole was significantly longer (2.59 vs 0.85 h), and peak plasma concentration of omeprazole (C(max)) was significantly higher (746 vs 311 ng/ml) than that in control group. The greater AUC and higher C(max) in treated group could be due to inhibition of omeprazole metabolism by fluconazole.     

On the antipyrine test in laboratory animals. Studies in the dog and monkey

The antipyrine (AP) test has been challenged in species other than humans on the grounds that, in some nonhuman species, particularly on induction, hepatic blood flow may become as prominent a factor in AP clearance as hepatic metabolism. Therefore, we investigated in dogs and monkeys the disposition of AP to determine how well AP serves as a model drug to indicate changes in rates of hepatic clearance. After administration of an oral solution of AP (5 mg/kg) to control dogs, the percentage of the dose absorbed was 98%, based on urinary and fecal excretion of AP and its metabolites. Despite complete AP absorption, absolute bioavailability of AP was 78 +/- 12% under basal conditions, suggesting that AP does undergo some degree of presystemic elimination, approximately 22%. After PB administration of 20 mg/kg/day for 9 days, po, AP bioavailability decreased to 60 +/- 14%. The systemic clearance of AP increased from 9.4 +/- 2.3 ml/min/kg under basal conditions to 27.5 +/- 4.6 ml/min/kg following PB. PB decreased mean plasma AP half-life from 71.5 min under basal conditions to 27.7 min, and mean hepatic blood flow increased from 0.49 liters/min to 0.63 liters/min. Induction doubled the hepatic extraction ratio for AP to 0.4 from 0.2 under basal conditions. In beagle dogs after PB pretreatment, 97% of the total systemic clearance of AP was estimated to be due to enhanced hepatic AP metabolism, only 3% to increased hepatic blood flow. Therefore, for dogs under both basal and induced conditions it is concluded that AP clearance reflects predominantly hepatic AP metabolism, being negligibly influenced by hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and tissue distribution of recombinant human tumor necrosis factor-alpha in mice

The serum pharmacokinetics and the major organs of accumulation of recombinant human tumor necrosis factor-alpha (rHuTNF) were determined in BDF1 mice after intravenous and intramuscular administration. Serum concentrations of immunoreactive protein were determined by enzyme-linked immunosorbent assay, and radioactivity was quantitated by beta and gamma scintigraphy. The serum pharmacokinetics of labeled and unlabeled rHuTNF were identical when administered by the intravenous route. After intravenous doses of 165 to 320 micrograms/kg, the clearance was 2.9-3.6 ml/hr, the initial volume of distribution was 1.4-1.6 ml (70-80 ml/kg), and the half-life was 18.5-19.2 min. Intramuscular administration of 320 micrograms/kg resulted in a peak serum concentration of 112 ng/ml. The time of the peak concentration was 1 hr, and the bioavailability of the intramuscular dose was 12%. The data suggest that the disposition of this protein may be biexponential. If this is the case, the terminal phase would appear to account for less than 1% of the total AUC. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported. 125I-Labeled and metabolically labeled 3H-rHuTNF were used to examine tissue distribution. After intravenous 125I-rHuTNF administration, the rank order of accumulation of the 125I-radiolabel in the major organs (per cent dose per organ over 1440 min) was: liver greater than kidney greater than lung greater than heart greater than spleen. This rank order of accumulation was confirmed by intravenous 3H-rHuTNF administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of nilvadipine, a new dihydropyridine calcium antagonist, in mice, rats, rabbits and dogs

1. The pharmacokinetics of nilvadipine in male and female rats, and in male mice, rabbits and dogs were studied after i.v. and oral dosing. 2. After i.v. dosing (0.1 mg/kg), the plasma concentrations of nilvadipine declined two- or three-exponential with terminal half-lives of 0.73 h in mice, 1.2 h in male and female rats, 3.7 h in rabbits and 5.0 h in dogs. Sex difference in pharmacokinetics after i.v. dosing in rats was not found. The systemic plasma clearance was in the order of mice greater than rats greater than rabbits greater than dogs, and nearly equalled the hepatic blood flow in each species. The volume of distribution at steady-state was high (greater than 4 L/kg) in all species. 3. After oral dosing, plasma concentrations of nilvadipine peaked within 1 h in all species except for middle and higher doses (4 and 16 mg/kg) in dogs. The area under the plasma concentration-time curves in male rats (3.2-100 mg/kg) and dogs (1-16 mg/kg) increased in proportion to the dose. Bioavailability was low in male rats (3-4%) and rabbits (2%), but in other species was 29-44%. The oral clearance in male rats was about 8 times higher than in female rats. 4. The free fraction of nilvadipine in plasma was 1.94% in mice, 1.89% in rabbits and 0.85% in dogs, with no dependence on plasma concentration over a range of 10-100 ng/ml.     

Pharmacokinetics and disposition of DY-9760e, a novel calmodulin antagonist, in rats and monkeys

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, CAS 162496-41-5) is a novel calmodulin antagonist that is being evaluated for the treatment of ischemia. The objective of this study was to characterize the pharmacokinetics and disposition of DY-9760e in rats and monkeys. After a 6 h continuous infusion at 1 mg/kg/h to male rats, the plasma concentration of unchanged DY-9760, as the anhydrous free base of DY-9760e, declined with a terminal half-life of 3.0 h. In monkeys, the plasma concentration of DY-9760 following a 4 h continuous infusion at 1 mg/kg/h declined with a terminal half-life of 3.8 h. Total clearance was 18.3 ml/min/kg in rats and 16.7 ml/min/kg in monkeys. The pharmacokinetics of DY-9760e was linear within a dose range from 1 mg/kg to 16 mg/kg in monkeys. After intravenous bolus administration of 14C-DY-9760e to rats, the radioactivity was widely distributed throughout the body except for the brain and testis. In the brain, which is the target organ of this compound, the concentrations of unchanged DY-9760 in rats were much lower than the corresponding plasma concentrations. These results indicated that the permeability of DY-9760 into the brain was restricted. In contrast, the brain concentrations of the N-dealkylated metabolite DY-9836 were approximately 2- to 3-fold higher than those observed in the plasma. The administered radioactivity was excreted mostly in the feces (95.2% in rats, 83.6% in monkeys), and the biliary excretion of the radioactivity in bile duct-cannulated rats was 86.2% within 48 h, part of which (11.1%) was re-absorbed. The urinary excretion of unchanged DY-9760 was less than 0.5% in both species. The metabolic profile characterized by thin-layer chromatography demonstrated that most of the radioactivity in the urine and bile referred to many polar metabolites. These results indicate that DY-9760e is eliminated mainly through hepatic metabolic clearance in both rats and monkeys.     

Clinical pharmacokinetics of clozapine in chronic schizophrenic patients

Summary The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.     

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone,in mice following intravenous administration

The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.     

Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788.

Following a single intravenous dose of 0.1 mg/kg, the pharmacokinetics of Ro 15-1788, a specific benzodiazepine antagonist, have been investigated in 20 healthy male volunteers. In random order injection of Ro 15-1788 has been preceded (5 min) by intravenous dosing with 0.06 mg/kg of lormetazepam (n = 6), 0.03 mg/kg of flunitrazepam (n = 8) or placebo (n = 6). The rapid elimination of the antagonist could be characterized by an elimination half-life between 0.9 to 1.4 h and a total plasma clearance of 727 to 1440 ml/min. These single dose studies indicate that the disposition of Ro 15-1788 was not affected by the acute coadministration of both benzodiazepines.     

Biopharmaceutic and pharmacokinetic aspects of vincamine HCl

Vincamine HCl was biopharmaceutically and pharmacokinetically evaluated. For biopharmaceutical characterization of the drug the apparent lipoid/water partition coefficient (APC), pKa, extent of protein (bovine) binding and the erythrocyte (human) uptake were determined. Vincamine has an APC of 2.05, a pKa of 6.17, is 64% bound to plasma proteins, and is about 6% bound to erythrocytes. Because the gerbil was used as model in pharmacodynamic studies, the pharmacokinetic drug disposition was determined in this species and compared to parameters reported in the literature for other species. The terminal half-life is about 1 hour, the apparent volume of distribution 2.9 L/kg, and the total clearance is about 33.3 ml/min/kg. The parameters are comparable to other species including man. The brain concentration is about 5-fold that in plasma. A therapeutic steady state concentration for effectiveness in gerbils has been estimated to be 0.02 mcg/ml.     

Disposition and antiarrhythmic effect of lorcainide.

The disposition and the antiarrhythmic effect of lorcainide (R 15,889) were investigated in 11 patients with ventricular premature beats (VPB) after a single intravenous dose of 100 mg or 2 mg/kg and after multiple intravenous and oral dosing. Pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, t 1/2 (alpha), was calculated as 0.3 +/- 0.1 hr (mean +/- SD) and the terminal half-life, t 1/2 (beta), varied independently of the dose and route of administration between 5.8 and 12.5 hr (7.8 +/- 2.5 hr). After the single intravenous dose total plasma clearance (Cl) ranged from 570 to 1670 ml/min (988 +/- 425 ml/min) while after multiple dosing Cl decreased to 666 +/- 27 ml/min. Comparison of the area under the curves during steady state (ss) indicated a complete bioavailability of multiple oral doses. After the single intravenous dose, VPB were diminished or reduced for about 4 hr if the plasma concentrations exceeded 120 to 150 ng/ml. During ss-therapy plasma levels fluctuated between 200 and 550 ng/ml with an effective prevention of arrhythmias. Thus, the new drug demonstrates a therapeutic range of approximately 150 to 400 ng/ml and oral therapy seems to be effective with 100 mg t. i. d.     

The pharmacokinetics of omeprazole in humans--a study of single intravenous and oral doses

The pharmacokinetics of omeprazole, hydroxyomeprazole, omeprazolesulfone, and "remaining metabolites" have been studied in eight young healthy subjects following an acute i.v. and oral dose of 10 and 20 mg of 14C-labeled drug, respectively. The oral dose was given as a buffered solution. Two subjects exhibited essentially higher and more sustained plasma levels of omeprazole than the others. This was due to a higher bioavailability, lower clearance, and longer t1/2 of omeprazole in these two subjects. Maximum concentration (0.7-4.6 mumol/L) was reached between 10 and 25 min after oral dosing. The median bioavailability was 39% (25-117%) and the median systemic plasma clearance was 624 ml/min (range of 59-828 ml/min). The corresponding t1/2 for the i.v. dose was 35 min (16-150 min) and 39 min (14-186 min) after oral administration. The drug was rapidly distributed to extravascular sites (mean t1/2 lambda 1 = 3.0 +/- 0.8 min). Mean Vss was 0.23 +/- 0.04 L/kg. Low systemic clearance of omeprazole was associated with a decreased formation rate of hydroxyomepraxole and "remaining metabolites" while omeprazolesulfone formation seemed to be less affected. However, there was a clear-cut correlation between the t1/2 of omeprazole and of its omeprazolesulfone metabolite, indicating that the elimination of these two compounds is mediated by the same isoenzyme. The mean urinary recovery of the radioactive dose during 96 h was 78.3 +/- 2.3 and 75.7 +/- 2.6% for the i.v. and oral dose, respectively. Insignificant amounts were due to unchanged drug and omeprazolesulfone. The excretion of hydroxyomeprazole during the first 12 h varied between 4.6 to 15.5% of a given dose. The mean recovery of radioactivity in the feces was 19.3 +/- 3.1% of a given i.v. dose and 18.2 +/- 2.3% when given orally. It is concluded that omeprazole is mainly eliminated metabolically and that there is a substantial interindividual variation in the rate of formation of primary and secondary metabolites. This variation in omeprazole disposition is probably of limited clinical importance. The half-life, with a maximum of approximately 3 h, is too short to cause accumulation when the drug is administered in a once-daily regimen.     

Pharmacokinetics of carbisocaine in rats and mice

[14C]carbisocaine, N-(2-(2-[1-14C]-heptyloxyphenylcarbamoyloxy)-propyl)-diethylammoni um chloride was administered to male Wistar rats, weighing 180-210 g IV in doses of 0.425, 1.425, 2.425 or 4.425 mg/kg or orally in a dose of 2.425 mg/kg. Extraction of carbisocaine from alkaline media into n-heptane was used for assessment of the unchanged drug in plasma, organs and excreta in predetermined time intervals. The two-way analysis of variance confirmed the insignificant effect of subject variability of experimental animals (p greater than 0.05) on plasma data after IV administration. Plasma data following the IV administration were approximated by a linear open two-compartment model with elimination from the central compartment. Regression analysis indicated linearity between carbisocaine plasma AUC and the IV administered dose within the range tested. The following model parameters were obtained: elimination half-life 161.2 +/- 37.5 min, total body clearance 59.5 ml/min/kg, distribution volume in steady state 5616.2 ml/kg and mean residence time 96.7 min. The systemic availability of the orally given carbisocaine was 45.2%, assessed by AUCpo/AUCiv (0-360 min). The brain uptake index of carbisocaine in relation to 3H2O was 57.7 +/- 3.9%. Whole body autoradiographs of mice injected with [14C]carbisocaine documented accumulation of 14C in gall and urinary bladder and in the gut contents and the effective placental barrier against carbisocaine and its metabolites.     

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.     

Pharmacokinetics and metabolism of the pharmacologically active 4'-hydroxylated metabolite of propranolol in the dog

The disposition of 4'-hydroxypropranolol (HOP) was determined after iv administration to dogs (2 mg/kg; N = 5) and the pharmacokinetic parameters were calculated from plasma measurements. The clearance of HOP, 66 +/- 6 ml/min/kg (mean +/- SE), was considerably higher than that of propranolol previously determined, suggesting extrahepatic as well as hepatic clearance of HOP. The plasma half-life of HOP, 77 +/- 6 min, was shorter than that of propranolol. Although HOP is considerably less lipophilic than propranolol, its volume of distribution, 6.4 +/- 0.8 liter/kg, surprisingly, was larger. Like propranolol, HOP appeared to be cleared entirely by metabolism. Whereas propranolol is metabolized mainly by oxidation, HOP was metabolized to sulfate (HOPS) and glucuronic acid (HOPG) conjugates. The plasma half-lives of these conjugates were 2 to 3 times longer than for HOP, reflecting a slow, continuous formation from HOP. This was established for HOPS by iv administration of synthetic HOPS. Morover, after HOP administration both formation and renal clearance of HOPS were stereoselective in favor of the R-enantiomer. In summary, the main conclusion of this study is that the large volume of distribution as well as high clearance through sulfation and glucuronidation may explain the low plasma HOP levels observed during propranolol therapy.