Pentachlorophenol toxicokinetics after intravenous and oral administration to rat.

1. The toxicokinetics of pentachlorophenol (PCP) were studied in rats. Doses of 2.5 mg/kg were given i.v. (bolus, five rats) and orally (gastric intubation, five rats). Concentrations in plasma, urine and faeces were measured by capillary g.l.c. with electron-capture detection. 2. After i.v. administration, the clearance and volume of distribution at steady state were 0.026 +/- 0.003 l/h per kg and 0.25 +/- 0.02 l/kg, respectively. These two parameters exhibit low inter-rat variability (coefficients of variation less than 15%). The half-life of the initial decline of PCP plasma concn. was less than 1.3 h, while the second phase half-life was 7.11 +/- 0.87 h. 3. After oral administration the peak plasma concn. (7.3 +/- 2.8 micrograms/ml) occurred between 1.5 and 2 h and absorption was complete (bioavailability = 0.91-0.97). No distinct distribution phase was observed and the elimination half-life was 7.54 +/- 0.44 h. 4. PCP clearance is essentially metabolic since only 5.3 +/- 0.2% dose is eliminated unchanged by the kidney. About 60% dose was recovered in urine, mainly as conjugated PCP and conjugated tetrachlorohydroquinone (TCHQ). 5. For both routes of administration, about 10% dose was recovered in faeces as PCP and/or metabolites, which indicates that biliary excretion contributes to total elimination.     

Presystemic and systemic intestinal metabolism of fenoterol in the conscious rat

The intestinal and liver first pass metabolism of fenoterol.HBr (Berotec, Partusisten) was investigated in the conscious rat. Fenoterol plasma concentrations (2-1000 ng/ml) were measured with a new HPLC determination using electrochemical detection. After intraduodenal administration, fenoterol was incompletely absorbed (47-66% not absorbed). Presystemic intestinal (EGpre) and liver (EH) extraction ratios, EGpre = 0.93 +/- 0.01, EH = 0.67 +/- 0.04, were calculated from AUC values after intraduodenal, intraportal, and iv administration. Saturation of intestinal and/or liver metabolism was checked by using three dose levels at different administration routes. Total systemic availability after intraduodenal administration ranged from 0.8 (10 mg/kg) to 1.2% (40 mg/kg). The contribution of the splanchnic region to the systemic clearance of fenoterol was assessed by measuring fenoterol and fenoterol-glucuronide concentrations in arterial and portal venous blood under steady state conditions. During iv infusion (30 micrograms fenoterol/min X kg), an intestinal extraction ratio of EG = 0.26 was observed. After iv administration of fenoterol (1 and 2 mg/kg), dose-dependent pharmacokinetics were observed. Doubling of the dose resulted in an increase of systemic clearance (Cl = 53.8 +/- 2.7 and 74.4 +/- 1.8 ml/min X kg) and distribution volume (Vss = 0.95 +/- 0.13 and 1.21 +/- 0.11 liters/kg); the mean residence time (17.9 +/- 2.4 and 16.3 +/- 1.4 min) and terminal half-life (45.8 +/- 5.5 and 46.8 +/- 2.8 min) were not changed.     

Clearance of cyclopentyladenosine and cyclohexyladenosine in rats following a single subcutaneous dose.

A(1)-adenosine receptor agonist N(6)-cyclopentyladenosine (CPA) (3.0 mg kg(-1) body weight), or N(6)-cyclohexyladenosine (CHA) (3.0 mg kg(-1) body weight) was subcutaneously (s.c.) administered as a single dose to rats. After that, the blood samples (150 microl) were collected from vena saphena into heparinized capillary tubes at the different time points. The concentrations of CPA and CHA were assayed by reversed-phase high performance liquid chromatography (HPLC). Based on the present study, the retention times for CPA and CHA were 3.029 +/- 0.017 min and 5.07 +/- 0.031 min, respectively. In addition, the maximum concentrations of CPA and CHA were measured 60 and 80 min after the administration, and the half-lives of these compounds in the circulation were approximately 48.5 +/- 4.4 min and 106.6 +/- 7.4 min, respectively. Presumably, the difference between these values due to the larger cycloalkyl substituent of CHA and different absorption properties of these compounds. Moreover, in the present study, the elimination half-life was approximately sevenfold longer than that previously reported for CPA (48.5 +/- 4.4 min versus 6.9 +/- 0.5] min). The discrepancy in the half-life is not surprising because the administration route was different. On the other hand, after the s.c. administration, the absorption rates of these adenosine analogues are known to be slow. Based on the results of this paper, the authors conclude that the half-life of CHA is approximately 2.2-fold compared to that of CPA.     

Pharmacokinetics of mebudipine, a new calcium antagonist, following single intravenous and oral administrations in rats

The pharmacokinetics of a new calcium antagonist, mebudipine, was studied after a single intravenous (0.5 mg/kg) and oral (10 mg/kg) administration to rats. After intravenous dosing, the plasma concentration of mebudipine declined biexponentially with a terminal half-life of 2.84 h. The blood clearance was 1.67 l/h/kg and the volume of distribution at steady state was found to be 6.26 l/kg. After oral dosing (10 mg/kg), the C(max) of mebudipine was 25.9+/-9.79 ng/ml. The oral bioavailability was low (< 2%) suggesting a marked first-pass effect. The distribution of mebudipine into some tissues such as brain, heart, liver and kidney following intravenous administration (0.5 mg/kg) was studied and a rapid distribution of mebudipine into these tissues was found. It was concluded that brain, heart, liver and kidney are in the same compartment as plasma (central).     

Evaluation of pharmacokinetics, brain levels and protein binding of centpropazine in rats

The pharmacokinetics of centpropazine (CNPZ), an antidepressant, was studied in rats. CNPZ was administered to groups of rats (n=3 to 5) via oral (40 mg/kg), intravenous (5 mg/kg), intraperitoneal (5 mg/kg) and intraduodenal (4 and 8 mg/kg) routes. The AUCs of CNPZ were estimated and the bioavailabilities were calculated. CNPZ was characterized by a short elimination half-life (39.5 min), a high clearance (118 ml/min/kg) and a relatively large volume of distribution (1945 ml/kg) after intravenous administration. After oral administration CNPZ exhibited a very low oral bioavailability ( approximately 0.2%). The total first pass effect (Egit+liver) was calculated as 98.7%. The bioavailability of CNPZ was similar when administered by intraduodenal and oral routes. CNPZ readily penetrated into the brain and reached Cmax by 30 min post oral dosing. About 92.0%+/-0.8% of the drug was bound to serum proteins. Low oral bioavailability of CNPZ following oral administration is likely due to its metabolism by intestinal mucosa and liver.     

The stereoselective disposition of disopyramide in the dog

The disposition of d-, 1-, and d,1-disopyramide was studied in 5 conscious dogs after intravenous administration (15 mg/kg) of each compound using a balanced crossover design. The clearance of d-disopyramide (15.4 +/- 5.10 ml/min/kg) was significantly greater than that of the l-isomer (9.45 +/- 2.52 ml/min/kg) (p < 0.001). The clearance of the d,1-mixture was intermediate between that obtained for the d- and l-isomers. The steady-state volume of distribution of the three compounds was similar (approximately 1.4 liters/kg). The elimination half-life reflected differences in clearance, being 76.4 +/- 7.30 min for d-disopyramide, 112 +/- 23.4 min for 1-disopyramide, and 97.2 +/- 15.1 min for d,1-disopyramide. The effect of general anesthesia with urethane and chloralose on the disposition of the compounds was also examined. General anesthesia decreased the clearance and increased the half-life of all three compounds. No consistent differences in the volume of distribution were observed with anesthesia as compared to control. Thus, there is stereoselective elimination of the optical isomers of disopyramide in the dog, and general anesthesia decreases the clearance of d-, 1-, and d,1-disopyramide.     

Pharmacokinetics of morphine after epidural administration in man

The concentration of morphine and morphine glucuronide in serum after epidural injection of 9 patients with aortic abdominal surgery was measured using gas chromatography-mass fragmentography. The decline of morphine serum concentration after epidural administration of 0.1 mg/kg was described by a bi- or triexponential decay equation with a mean terminal half-life (t1/2) of 134.7 +/- 107.9 min. Pharmacokinetic parameters were calculated from the fit parameters mean values for clearance and apparent volume of distribution were 1.16 +/- 0.65 l/min, and 156.6 +/- 107.3 l, respectively, for free morphine and 0.19 +/- 0.09 l/min and 37.2 +/- 17.7 l, respectively, for morphine glucuronide. Peak concentration of morphine 79 +/- 19 ng/ml was reached within 10 min after administration. Haemodynamic values, ECG, end-expiratory CO2 concentration, temperature, acid-base status, hemoglobin, Na+, K+, total Ca++, lactate, glucose concentration in the blood and the urine were registered before, during and after the operation.     

Pharmacokinetics of postoperative intravenous indomethacin in children

The disposition of indomethacin was studied in children aged one to four years. Indomethacin 0.35 mg/kg was administered as an intravenous infusion during 15 min. Venous blood samples were collected until 24 hr after infusion. Serum indomethacin was determined with gas chromatography. Using a non-linear regression analysis, the individual data were fitted by a two-compartment open mammillary model with central elimination. Calculated pharmacokinetic parameters were (mean +/- SD); alpha half-life 25.2 +/- 11.3 min; beta half-life 366 +/- 295 min; steady-state volume of distribution 0.74 +/- 0.75 l/kg; volume during elimination phase 1.53 +/- 1.27 l/kg; total body clearance 3.2 +/- 1.7 ml/min./kg. Accordingly, with respect to the pharmacokinetics of indomethacin, children seem to mature early, not later than at the age of one year.     

Metabolism and pharmacokinetics of S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine in rats

The metabolism and pharmacokinetics of a mixed disulfide S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC) were studied in rats. Two metabolites of AC-DDTC following i.v. and p.o. administration were identified in plasma and liver by HPLC and GC, namely N,N-diethyldithiocarbamate (DDTC) and the methyl ester of DDTC (Me-DDTC). AC-DDTC was very unstable in vivo and could not be detected neither in plasma nor in urine. Pharmacokinetic parameters of DDTC following intravenous administration of AC-DDTC (20 mg/kg) were calculated. DDTC has a low affinity to rat tissue and the total body clearance was 9.0 +/- 3.4 ml/min/kg. The mean residence time (MRT) was 111.5 +/- 16.3 min. After oral administration of 20 mg/kg AC-DDTC, maximal plasma concentration (Cmax) was 3.8 +/- 0.2 nmol/ml and the bioavailability was 7.04%. Cmax for DDTC at a dose of 120 mg/kg AC-DDTC was 40.1 +/- 2.2 nmol/ml. MRT was 47.1 +/- 2.8 min at a dose of 20 mg/kg and 110.5 +/- 6.0 min at 120 mg/kg.     

Pharmacokinetics of D(+)-usnic acid in rabbits after intravenous and oral administration.

The pharmacokinetics of D(+)-usnic acid--a lichen antitubercular, antitumor, and enzyme-inhibiting agent--was studied in rabbits following intravenous or oral administration of 5 and 20 mg/kg body weight doses, respectively. Plasma samples were collected at different time intervals, and usnic acid was determined by HPLC. Plasma usnic acid levels following intravenous administration showed a triexponential elimination with a mean +/- SD terminal half-life of 10.7 +/- 4.6 hr. The volume of distribution of the central compartment and systemic clearance were 43.9 +/- 21.3 ml/kg and 12.2 +/- 3.0 ml/hr/kg, respectively. Pharmacokinetic parameters obtained, based on compartmental and noncompartmental approaches, were comparable. Plasma concentration data obtained after oral administration were analyzed using a noncompartmental method. Peak plasma level (Cmax) of 32.5 +/- 6.8 micrograms/ml was achieved in 12.2 +/- 3.8 hr (tmax). Mean absolute bioavailability of usnic acid following oral administration was 77.8%.     

Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half-life was 15.09 +/- 0.68 h (mean +/- s.e. mean) (RI) and 12.9 +/- 1.0 h after dialysis (RD), but there was a significant decrease in half-life during dialysis (4.25 +/- 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/- 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/- 0.09 l/kg) and female patients (0.59 +/- 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half-life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half-life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/- 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half-dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.     

A TRH analog (DN-1417). Blood level and brain distribution determined by radioimmunoassay after intravenous administration in rats

Thyrotropin-releasing hormone (TRH) and its analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), were administered intravenously to rats, and the blood level and brain distribution were determined by a specific radioimmunoassay. Degradation half-life of DN-1417 in the brain homogenate and blood was 27.5 min and those of TRH were 5 and 7.5 min, respectively. After the administration of DN-1417 (0.625, 2.5 and 10 mg/kg), the blood levels of immunoreactive-DN-1417 exhibited an apparent two compartment open model. The half-life values of the alpha- and beta-phase were 3 approximately 7 and 15 approximately 22 min, respectively. The half-life of the blood level of immunoreactive-DN-1417 was 2 approximately 3 times longer than that of TRH. As a result, the area under the curve of DN-1417 was 2.5 approximately 6 times larger than that of TRH. Blood level of immunoreactive-2-hydroxy-4-carboxybutyryl-histidyl-prolinamide+ ++ (DN-COOH), a main metabolite of DN-1417, was not more than 1% of the immunoreactive DN-1417 level. The distribution of DN-1417 into whole brain was attained its peak at 1 approximately 2 min after the administration. The percentage of transported DN-1417 into the brain at peak time was 0.062-0.163% of each of the doses administered. After the administration of DN-1417 (2.5 mg/kg), the pituitary, nucleus accumbens and hypothalamus showed higher concentrations, while the striatum showed the lowest concentration in the brain tissue examined.     

Intravenous pharmacokinetics of ciprofloxacin in goats

The pharmacokinetics of ciprofloxacin in goats was studied following intravenous administration. A single dose of 10 mg/kg was administered as an intravenous bolus, and serum samples were collected at predetermined intervals over a 24 h period. Ciprofloxacin levels were measured using high pressure liquid chromatography and the resulting concentration versus time curve was analyzed using a non linear regression analysis. The data were best represented by a two-compartment pharmacokinetic model with a mean elimination half-life of 2.72+/-1.04 h. Mean pharmacokinetic parameters obtained were area under the curve (AUC: 10.320+/-5.137 microg/ml per h), mean residence time (MRT: 3.334+/-1.428 h), apparent volume of distribution (Vdss: 3.373+/-0.893 l/kg) and total body drug clearance (tCl 19.596+/-9.059 ml/min per kg). Ciprofloxacin in goats showed the general pharmacokinetic characteristics of a typical fluoroquinolone antibacterial agent and we recommend a dose of 10 mg/kg to be administered intravenously at 12 h intervals to goats.     

Pharmacokinetics and tolerance of repeated oral doses of loxiglumide

The study was conducted on 6 adult healthy subjects (5 males and 1 female) in order to investigate the pharmacokinetics and tolerance of repeated b.i.d. oral administration for 7 days of tablets containing 400 mg of loxiglumide (CR 1505). The pharmacokinetics of loxiglumide in plasma after the first single dose of 400 mg is characterized by a lag time of 16 +/- 4 min, a rapid invasion (kinv = 10 h-1), a Cmax of 11.9 +/- 5.1 mg/l at tmax of 2.3 +/- 0.8 h, a mean residence time (MRT) of 6.9 +/- 1.1 h and an AUC of 60.6 +/- 16.3 (mg/l) x h. After the last dose of 400 mg the lag time was 17 +/- 6 min, the Cmax 12.7 +/- 3.8 mg/l at tmax of 2.1 +/- 0.8 h, a MRT of 11.0 +/- 1.9 h and an AUC of 109.8 +/- 39.9 (mg/l) x h. The increases of the AUC and of MRT were statistically significant and are probably due to an accumulation of loxiglumide which occurs during the repeated dose course and reaches the steady state within 48 h of repeated administration. Due to this accumulation the Cmax increased by 7%. The increase was not statistically significant or clinically relevant. No dose adjustment seems required during a repeated dose dosing schedule with 400 mg b.i.d. In the urine loxiglumide and 3 metabolites were found, which were called Metabolite (Met.) 11.2, Met. 12.0 and Met. 12.8. Met. 12.0 was the most abundant, accounting for 45% of the loxiglumide related substances excreted in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of diminazene in sheep

The pharmacokinetic behavior of diminazene in plasma after administration of 2 mg/kg i.v. and 3.5 mg/kg i.m. was studied in four healthy Dala x Ryggja rams. Following i.v. injection, the data were satisfactorily described by a tri-exponential equation; the apparent volume of distribution at the steady-state was 0.56 +/- 0.04 L/Kg (mean +/- SD; n = 4); total body clearance averaged 1.1 +/- 0.09 ml/kg/min and elimination half-life was 9.30 +/- 1.40 hr. After intramuscular administration peak plasma levels of 6.30-7.57 micrograms/ml were reached in 20 to 45 min and the mean absorption time averaged 5.83 +/- 1.61 hr. Systemic availability relative to the intravenous dose was 95.10 +/- 23.21% and mean residence time averaged 14.16 +/- 1.55 hr. The partition of diminazene between erythrocytes and plasma averaged 0.64 +/- 0.10; plasma protein binding was high (65-85%) and concentration-dependent. Based on the experimental data obtained, an initial i.m. dose of 2.5 mg/kg followed by 2 mg/kg 24 hr later should be safe and effective in cases of babesiosis and trypanosomiasis sensitive to diminazene. A preslaughter withdrawal period of 14-26 days was estimated.     

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].     

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.     

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.     

Pharmacokinetics and tissue distribution of a new heterocyclic N-phenylpiperazine derivative (LASSBio-581) in rats.

This work investigated the pharmacokinetics of a new N-phenylpiperazine derivative (LASSBio-581), active on dopaminergic system. LASSBio-581 plasma concentrations were determined in rats after bolus administration of 10mg/kg, i.v., 30 and 60 mg/kg, i.p. and p.o., by HPLC. Individual profiles were evaluated by non-compartmental and compartmental analysis using WinNonlin. Protein binding by ultrafiltration showed free fraction of 29+/-4%. The compound showed linear pharmacokinetics for the extravascular doses investigated. The oral bioavailability ( approximately 25%) was approximately half of the intra-peritoneal one ( approximately 47%). The 60 mg/kg oral dose showed an unusual profile with two peaks (1 and 6h). A two-compartment model better described all plasma profiles. The Vd (0.8+/-0.4l/kg) and the t(1/2) (1.2+/-0.4h) were smaller for i.v. than for the other routes. The CL(tot) was statistically similar for all three administration routes investigated (0.6+/-0.2l/(hkg)) (alpha=0.05). The compound distribution into different organs, evaluated in tissue homogenates after i.v. administration, showed a higher penetration in lungs (51.0%), followed by the brain (39.2%), where the half-life was three times bigger than in the other tissues (1.9h). The compound brain profile agreed with the central nervous system activity determined.