Species differences in pharmacokinetics of a hepatoprotective agent, YH439, and its metabolites, M4, M5, and M7, after intravenous and oral administration to rats, rabbits, and dogs

Pharmacokinetic parameters of YH439 and its metabolites, M4, M5, and M7, were compared after iv administration of YH439 to rats (1-10 mg/kg), rabbits (1-10 mg/kg), and dogs (1-20 mg/kg) and oral administration of YH439 to rats (50-500 mg/kg) and dogs (0.5-2 g per whole body weight). After oral administration of YH439 to rats, the F values were 3.67, 1.33, and 0.859% for YH439 oral doses of 100, 300, and 500 mg/kg, respectively. However, the F value increased significantly, 21.2%, after oral administration of YH439-contained mixed micelles (10 mg as free YH439) to rats due to increased water solubility of YH439. Species differences in the pharmacokinetics of YH439 and its metabolites were found. First, M7 was detected in both plasma and urine after both iv and oral administration of YH439 to dogs, whereas it was detected neither in rats nor in rabbits, indicating that considerable amount of M7 was formed from YH439 only in dogs. Second, the AUC (or AUC0-->t) ratios of M4 to YH439 after iv administration of YH439 were 24.6-31.3, 42.2-49.2, and 2200-7640% for rats, rabbits, and dogs, respectively, indicating that formation of M4 after iv administration of YH439 was maximal in dogs. Third, the AUC (or AUC0-->t) ratios of M5 to YH439 after iv administration of YH439 were 103-127, 2.93-3.31, and 92.4-158% for rats, rabbits, and dogs, respectively, indicating that formation of M5 after iv administration of YH439 was minimal in rabbits.     

Disposition of [14C]avitriptan in rats and humans

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans. The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans. Renal excretion was a minor route of elimination in both species, with the majority of the dose being excreted in the feces. After a single oral dose, urinary excretion accounted for 10% of the administered dose in rats and 18% of the administered dose in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats. Avitriptan was extensively metabolized after oral administration, with the unchanged drug accounting for 32% and 22% of the total radioactivity in plasma in rats and humans, respectively. Plasma terminal elimination half-life was approximately 1 hr in rats and approximately 5 hr in humans. The drug was extensively distributed in rat tissues, with a tendency to accumulate in the pigmented tissues of the eye.     

Pharmacokinetics of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1- piperazinyl)-1,4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride (DW-116), a new quinolone antibiotic in rats

The objectives of this study were to characterize the pharmacokinetics of 1-5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1- piperazinyl)-1,4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride (DW-116), a newly developed quinolone antibiotic, and to compare these kinetics with those of ciprofloxacin and rufloxacin, representative quinolone antibiotics, in rats. Rats were subjected to surgery involving catheterization of the femoral vein and artery. DW-116 (4, 20, or 200 mg/kg), ciprofloxacin (20 mg/kg), or rufloxacin (20 mg/kg) was administered either intravenously (iv) or orally. Blood samples were collected at various times and subjected to an HPLC assay for the quinolones. Temporal profiles of plasma concentration after iv administrations of DW-116 at doses of 4, 20, and 200 mg/kg exhibited an apparent multiexponential decline. In the three doses examined, systemic clearance and steady-state volume of distribution of DW-116, calculated by model-independent methods, were in the range 0.17 approximately 0.23 L/h/kg and 2.90 approximately 4.44 L/kg, respectively. When DW-116 was given orally at doses of 4, 20, or 200 mg/kg, the AUC values were nearly identical to those following iv administration, indicating an almost complete absorption (i.e., the percent bioavailability was 90.0 for 4 mg/kg, 99.0 for 20 mg/kg, and 98.3 for 200 mg/kg) in the dose range examined. The absorption of DW-116 appears to be extremely rapid because the mean residence time calculated from the oral administration data was not significantly different from that for the iv administration. At a dose of 20 mg/kg, the mean residence time for iv administered ciprofloxacin and rufloxacin was smaller than that of DW-116, indicating that DW-116 remains in the body longer than the other quinolones. Absolute percent bioavailabilities of ciprofloxacin (69.9%) and rufloxacin (84.9%) were smaller than that obtained for DW-116 (99.0%). Because it has been reported that the in vivo antibacterial activity of DW-116 is comparable or superior to that of rufloxacin and ciprofloxacin, despite the fact that the in vitro activity is significantly lower, the pharmacokinetics of this antibiotic may be responsible, at least in part, for the enhanced in vivo antibacterial activity of DW-116.     

Circadian changes in the pharmacokinetics and pharmacodynamics of azosemide in rats

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg(-1)) to rats at 1000 or 2200 h. After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CLR) of azosemide was significantly faster (2.86 compared with 1.76 mL min(-1) kg(-1)) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CL(R) of azosemide was significantly faster (3.64 compared with 0.79 mL min(-1) kg(-1)) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats. If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.     

Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 1st communication: absorption, concentrations in plasma, metabolism, and excretion after single administration to rats and dogs

The absorption, concentrations in plasma, metabolism and excretion of ramatroban ((+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid, CAS 116649-85-5, BAY u 3405) have been studied following a single intravenous, oral, or intraduodenal administration of 14C-labeled or nonlabeled compound to rats and dogs (dose range: 1-10 mg.kg-1). After intraduodenal administration of [14C]ramatroban, enteral absorption of radioactivity was rapid and almost complete both in bile duct-cannulated male rats (83%) and female dogs (95%). The oral bioavailability of ramatroban was complete in the dog but amounted to about 50% in the rat due to presystemic elimination. A marked food effect on the rate but not on the extent of absorption was observed in rats. The elimination of the parent compound from plasma occurred rapidly with total clearance of 1.2 l.h-1.kg-1 in male rats and 0.7 l.h-1.kg-1 in dogs. After oral administration to male rats AUC increased dose-proportionally between 1 and 10 mg.kg-1, whereas in Cmax an over-proportional increase was observed. Excretion of total radioactivity was fast and occurred predominantly via the biliary/fecal route in both species. The residues were low, 144 h after dosing less than 0.2% of the radioactivity remained in the body of rats. A considerable sex difference was found in rats following oral administration of ramatroban. In females a 3-fold higher AUC and a 1.7-fold longer half-life of unchanged compound, as well as 3-fold higher renal excretion of total radioactivity was observed. A marked species difference exists in the metabolism of ramatroban. In dogs the drug was almost exclusively metabolized via conjugation with glucuronic acid, whereas in rats oxidative phase I metabolism and glucuronidation were equally important. As a consequence enterohepatic circulation was much more pronounced in dogs (77%) than in rats (17% of the initial dose).     

Pharmacology and toxicology of artelinic acid: preclinical investigations on pharmacokinetics, metabolism, protein and red blood cell binding, and acute and anorectic toxicities

The pharmacokinetics, metabolism, protein binding, red blood cell (RBC) binding, stability in vitro, and acute and anorectic toxicity of artelinic acid (ARTL) were investigated in various animal species and human blood samples. Absorption and distribution following 10 mg/kg intramuscular or oral administration in dogs and rats were very rapid with t1/2 0.12-0.54; there were also a high AUC (11,262 ng/h/mL) and Vss (9.5 L/kg), low CL (15 mL/min/kg) and long elimination time (t1/2 = 2.6 h), compared with rat data. Oral bioavailability of ARTL was 79.7% in dogs and 30.1% in rats. The conversion of ARTL to dihydroartemisinin (DART) in dogs (0.1-0.5% of total dose) after 3 routes of administration (intravenous, intramuscular and oral) was 10-fold lower than that in rats. In rats dosed with [14C]ARTL, unchanged ARTL accounted for less than 13% of the total radioactivity after all 3 administration routes, suggesting that ARTL was extensively biotransformed. The half-lives of total radioactivity (21-49 h) in urine were much longer than that of unchanged ARTL in plasma (1.4-3.7 h), indicating that some long-lasting metabolites of ARTL were formed in rats. The mass balance data showed that 77-83% of total radioactivity was recovered in urine and faeces. High binding capacity (79-95%) and low binding affinity (1.1-9.3 x 10-7 M) of ARTL were measured in rat, rabbit, dog, monkey and human plasma. The RBC/plasma ratios of [14C]ARTL were 0.35 and 0.44 for dog and human plasma, respectively. ARTL was much more stable than artesunic acid (ARTS) in rat and dog plasma, and both ARTL and ARTS were more stable in dog plasma than in rat plasma in vitro. The 50% lethal dose (LD50) of ARTL in rats was about 535 mg/kg. Multiple intramuscular dosing for 7 d of 50 mg/kg/d of ARTL caused mild anorectic toxicity compared to ARTS in rats. In contrast to 4 other artemisinin derivatives, ARTL seems to be a good antimalarial candidate as it has the highest plasma concentration, the highest binding capacities in RBC, the highest oral bioavailability, the longest elimination half-life, the lowest metabolism rate and the lowest toxicity at equivalent dose levels.     

In vivo disposition and metabolism by liver and enterocyte microsomes of the antitubercular drug rifabutin in rats

The in vivo disposition and in vitro metabolism of rifabutin, a new spiropiperidylrifamycin, were studied in rats and in microsomes from rat liver and enterocytes, respectively. After i.v. doses of 1,5, 10 and 25 mg/kg the systemic clearance was 0.7 to 1.0 liters/hr/kg; the volume of distribution was 4.4 liters/kg for the 1 mg/kg dose and 7.4 to 7.7 liters/kg for the 5 to 25 mg/kg doses, and the half-life ranged from 4.4 to 9.1 hr. Urinary and fecal excretion over 0 to 96 hr after i.v. administration of 25 mg/kg [14C]rifabutin accounted for 40.1 and 52.2% of the dose, respectively. Exteriorization of the bile duct showed that approximately 24% of the dose was eliminated in bile, > or = 98% as metabolites. Bioavailability after oral administration of 25 and 1 mg/kg rifabutin was > 90% and 44%, respectively, suggesting significant first-pass metabolism of the lower dose. Concentrations of rifabutin in gastric juice were 10 to 17 times higher than in blood, indicating extensive secretion into the stomach. Experiments with the isolated small intestinal loop demonstrated direct exsorption of the drug into the lumen. The rate of rifabutin metabolism by enterocyte microsomes was > 10 times higher than that by liver microsomes, i.e., 84 and 8 pmol/min/mg protein, respectively. Biotransformation of rifabutin in vivo and in vitro was markedly induced by dexamethasone and inhibited by erythromycin, suggesting that CYP3A is involved in the metabolism of rifabutin. Several metabolites, including 20-OH-rifabutin and 27-O-demethyl-rifabutin, isolated from urine and microsomes were identified by mass spectrometry and nuclear magnetic resonance spectroscopy.     

Pharmacokinetics of methyl palmoxirate, an inhibitor of beta-oxidation, in rats and humans

Recent studies from our laboratory have shown that methyl palmoxirate (MEP), an inhibitor of mitochondrial beta-oxidation of long chain fatty acids, can be used to increase incorporation of radiolabeled palmitic acid into brain lipids and reduce beta-oxidation of the fatty acid. Thus, MEP allows the use of carbon labeled palmitate for studying brain lipid metabolism in animals and humans by quantitative autoradiography or positron emission tomography (PET). As it is essential to pretreat human subjects with an acute dose of MEP prior to intravenous injection of [1-11C]palmitate for PET scanning, this study was undertaken to determine the plasma elimination half-life of MEP in rats and human subjects and to provide insight about the drug's absorption and metabolism. A gas chromatographic method was developed to measure MEP in body fluids. Following oral administration of MEP to rats (2.5 and 10 mg/kg) and to humans, the unmetabolized drug could not be detected in plasma or urine (sensitivity of detection was 1 ng). However, when MEP was injected intravenously (10 mg/kg) in rats, a peak initial concentration could be measured in plasma (7.7 microg/mL), the clearance of the drug from plasma was rapid (t1/2 = 0.6 min), which indicates that MEP readily enters tissue lipid pools or is metabolized like long-chain fatty acids. As no adverse experience occured in the 11 human subjects studied, oral administration of a single dose of MEP was safe under the conditions of this study and may be used to increase the incorporation of positron labeled palmitic acid for studying brain lipid metabolism in vivo by PET.     

Toxicokinetics of oxazepam in rats and mice

The comparative toxicokinetics of oxazepam were studied in F344 rats, B6C3F1 mice, and Swiss-Webster mice of both sexes after an i.v. dose of 20 mg/kg and oral gavage doses of 50, 200, and 400 mg/kg. In addition, the toxicokinetics of oxazepam in a 3-week dosed-feed study of male B6C3F1 mice at 125 and 2500 ppm were also investigated. Results indicated that the elimination of oxazepam from plasma after i.v. injection in both rats and mice were first-order and could be best described by a two-compartment model with a terminal elimination half-life of 4-5 h for rats and 5-7 h for mice. After oral gavage dosing the peak oxazepam plasma concentrations in most rodents were reached within 2-3.5 h. At all doses studied, female rodents had significantly higher plasma concentrations than males. Absorption of oxazepam was significantly extended at higher oral doses of 200 and 400 mg/kg. At 50 mg/kg, the bioavailability of oxazepam in rats (< 50%) was lower than in Swiss-Webster mice (> 80%). The bioavailability of oxazepam in both B6C3F1 and Swiss-Webster mice decreased with increasing dose. A dose proportionality of Cmax was not observed in rats and mice after gavage doses of 50, 200, and 400 mg/kg. Plasma concentrations of oxazepam in the dosed-feed study increased with the concentration of oxazepam in the feed, a quasi-steady-state of plasma concentrations of oxazepam was reached after approximately 4 days ad libitum exposure. In B6C3F1 mice, the estimated relative bioavailability of oxazepam from dosed feed (relative to gavage study at 50 mg/kg) was about 43%.     

Absorption of the anxiolytic pazinaclone in animals as a criterion for species selection for toxicity studies

In rats, mice, hamsters, and guinea pigs given a 5 mg/kg oral dose of pazinaclone (CAS 103255-66-9), unchanged drug concentration in plasma was highest in mice (AUC; 90 ng.h/ml), followed in decreasing order by guinea pigs (AUC; 41 ng.h/ml), hamsters (AUC; 18 ng.h/ml), and rats (AUC; 17 ng.h/ml). In terms of plasma drug concentrations and toxicological background data, there was no better alternative rodents than mice and rats for the toxicity studies. Among rabbits, dogs, and monkeys, the dogs had the highest plasma drug concentrations: AUCs of pazinaclone in dogs and monkeys were 1035 and 458 ng. h/ml, respectively (drug concentration in rabbit plasma was very low). Of the two polymorphs, forms 1 and 2 with particle size of < or = 5 microns, the oral absorption of form 2 in rats was more efficient than that of form 1 at 1000 mg/kg: AUCs of pazinaclone after dosing of form 1 and 2 were 489 and 965 ng.h/ml, respectively. However, form 1 was selected for the toxicity studies because of the poor physico-chemical properties of forms 2. Form 3 was not included in this study, because this form was relatively unstable and contained relatively large amount of impurities. The absorption of pazinaclone in dogs was improved by decreasing its particle size: AUCs of pazinaclone after dosing of the drug having particle size of 5.5, 20.8, and 79.3 microns were 1361, 822, and 297 ng.h/ml, respectively. Since large-scale preparation of bulk pazinaclone with a particle size of 5 microns or smaller was not feasible, the drug having a particle size of about 20 microns was used in the toxicity studies. The absorption of pazinaclone was more extensive when the drug was given to fed animals as suspension. Thus, the toxicity studies were performed using form I of pazinaclone with a particle size of about 20 microns primarily in rats, mice, and dogs.     

Diazinon toxicokinetics, tissue distribution and anticholinesterase activity in the rat

The toxicokinetics, tissue distribution, and anticholinesterase (antiChE) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after i.v. administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following i.v. and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailability was found to be low (35.5%). Hepatic extraction ratios after i.v. administration of 5 or 10 mg/kg were 54.8% and 47.7%, respectively, suggesting that low systemic oral bioavailability can be explained by a first-pass effect in the liver. Diazinon was found to be approximately 89% protein-bound in plasma within the concentration range 0.4-30 ppm. The highest concentration of diazinon after i.v. administration was found in the kidneys, when comparing to liver, kidney, brain. Both red blood cell (RBC) acetylcholinesterase (AChE) and plasma ChE activities were inhibited rapidly (44% and 17% at 10 min, and 36% and 13% min for i.v. and oral administration, respectively), but inhibition of RBC AChE was greater than that of plasma ChE.     

The pharmacokinetics of a new antiglaucoma drug, latanoprost, in the rabbit

Latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2alpha-1-isopropyl ester) is a unique prostaglandin analogue developed for the treatment of glaucoma. To investigate the pharmacokinetics, tritium-labeled latanoprost was administered topically on the eyes of rabbits and intravenously. About 7.7% of the applied dose was found in the cornea at 15 min after the drug administration. The following Cmax and elimination half-life (interval 1-6 hr) values of the total radioactivity in the eye tissues were found: aqueous humor, 0.09 ng eq/ml and 3.0 hr; anterior sclera, 1.49 ng eq/mg and 1.8 hr; cornea, 1.59 ng eq/mg and 1.8 hr; ciliary body, 0.39 ng eq/mg and 2.8 hr; conjunctiva, 1.41 ng eq/mg and 1.4 hr; and iris, 0.39 ng eq/mg and 2.1 hr. Latanoprost was rapidly hydrolyzed, and most of the radioactivity found in the aqueous humor, anterior eye tissues, and plasma corresponded to the pharmacologically active acid of latanoprost. The initial plasma elimination half-life of the acid of latanoprost was 9.2 +/- 3.2 min after iv and 2.3 +/- 1.9 min after topical administration on the eyes. The plasma clearance of the acid of latanoprost was 1.8 +/- 0.3 liters/hr.kg, and the volume of distribution was 0.4 +/- 0.1 liter/kg after iv administration. Based on the retention times on HPLC and GC-MS, the main metabolite in urine and feces was identified as the 1,2,3,4-tetranor metabolite of acid of latanoprost. This acid existed in equilibration with the corresponding delta-lactone. The AUC of radioactivity in the eye tissues was approximately 1000 times higher than in plasma AUC. The recovery of radioactivity was complete.     

Pharmacokinetics of acetaminophen after intravenous and oral administration to spontaneously hypertensive rats and normotensive Wistar rats

In our previous study, we reported the faster metabolism of intravenously administered furosemide, hence the smaller diuretic effect of furosemide in spontaneously hypertensive rats (SHRs) of 16 weeks of age than in the age-matched normotensive Wistar rats. In present study, in order to evaluate whether there is some alteration of the phase II metabolism including glucuronide and sulfate conjugations in 16-week-old SHRs and the age-matched Wistar rats, the pharmacokinetic parameters of acetaminophen (A), A-sulfate, and A-glucuronide were investigated after intravenous (iv) and oral 100 mg/kg administration of A to 16-week-old SHRs and the age-matched Wistar rats. After iv administration of A, the mean fraction of iv dose excreted in 24-h urine as A-sulfate (75.6 versus 67.8%) and the partial clearance of A to A-sulfate (8.10 versus 6.89 mL/ min/kg) were significantly greater in SHRs than in Wistar rats. Conversely, the mean fraction of iv dose excreted in 24-h urine as A-glucuronide (9.39 versus 15.0%) and the partial clearance of A to A-glucuronide (1.01 versus 1.49 mL/min/kg) were significantly smaller in these SHRs. Similar results were also obtained after oral dosing of A. The in vitro sulfotransferase activity toward A was significantly smaller (0.397 versus 0.331 microg/min/mg of protein) in 16-week-old SHRs than in the age-matched Wistar rats, whereas, the glucuronyltransferase activity toward A was not significantly different between these SHRs and Wistar rats. On the other hand, there was no significant difference in the both sulfotransferase and glucuronyltransferase activity toward A between 6-week-old SHRs and age-matched Wistar rats. Therefore, the alterations in sulfation and perhaps glucuronidation of A between 16 -week-old SHRs and normotensive Wistar rats suggested that some physiological factors derived from the chronic hypertensive status in SHRs might affect the disposition of drugs.     

Pharmacokinetic studies of pentylenetetrazol in dogs

Pharmacokinetic profiles of pentylenetetrazol in the dog were studied following rapid intravenous and oral administrations of a convulsant dose (15-20 mg/kg). Plasma level-time curves after a rapid intravenous injection showed biexponential decline, indicating that the disposition of this drug in the dog follows a two-compartment body model. Pharmacokinetic parameters were calculated from the intravenous data. After oral administration of the solution dose, the peak plasma level appeared at about 30 min postdose, indicating that the absorption occurs rapidly. Areas under the oral plasma level-time curves s howed that the drug was absorbed completely and that the first-pass metabolism effect was minimal. The ligation studies of the kidney and the liver suggested that the main elimination pathway of this drug was biotransformation in the liver. The average plasma half-life was 1.4 hr. At steady state, the volume of distribution was approximately equivalent to the volume of the total body water.     

Road traffic mortality in Victoria: an exploratory investigation into successful strategies

The recovery of radioactivity from plasma, urine and feces was determined in rats after administration of oral and intravenous doses (200 mg/kg) of 14C-labeled sodium gamma-hydroxybutyric acid. Very small portions of the radioactive dose were recovered in the urine (5.5%, oral; 7.1%, intravenous) and feces (1.5% oral; 0.6%, intravenous) collected between 0-48 hours after drug administration. Considerable levels of radioactivity were found in the plasma after oral dosing. The area under the plasma radioactivity time curve after an oral dose was found to be 65% of that observed after an equivalent intravenous dose. This value is much larger than the relative area value (8%) calculated on the basis of free gamma-hydroxybutyric acid. Results of this study strongly indicate that first-pass metabolism, rather than lack of absorption, is responsible for the apparently poor oral bioavailability of gamma-hydroxybutyric acid.     

Safety and pharmacokinetics of CS-834, a new oral carbapenem antibiotic, in healthy volunteers

CS-834, (+)-[pivaloyloxymethyl (4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(R)-5-oxopyrroli din-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate], is an ester-type oral carbapenem prodrug, and an active metabolite is R-95867, which has antibacterial activity. CS-834 was administered orally to healthy male volunteers at single doses of 50, 100, 200, and 400 mg and at a multiple dose of 150 mg three times a day for 7 days to investigate its safety and pharmacokinetic profiles. Other studies were conducted to examine the effect of food intake on the bioavailability of CS-834 and also the effect of the coadministration of probenecid on the pharmacokinetics of CS-834. In the fasting state, the concentration of R-95867 in plasma reached maximum levels from 1.1 to 1.7 h after the oral administration of CS-834, followed by a monoexponential decrease. The maximum concentrations of R-95867 in serum (C[max]s) after the administration of CS-834 at doses of 50, 100, 200, and 400 mg were 0.51, 0.97, 1.59, and 2.51 microg/ml, respectively. The half-lives (t1/2s) were almost constant, approximately 0.7 h. The areas under the concentration-time curves (AUCs) were proportional to the doses, ranging from 50 to 400 mg x h/ml. The cumulative recoveries in urine were approximately 30 to 35% until 24 h after drug administration. The C(max), AUC, t1/2, and recovery in urine were not affected by food intake. Probenecid coadministration prolonged the t1/2, and it increased the C(max) and AUC for R-95867 by approximately 1.5- and 2.1-fold, respectively. The multiple-dose study showed no change in the pharmacokinetics from those for the single doses and no drug accumulation in the body. A mild transient soft stool was observed in one volunteer in the study with a single dose of 400 mg. In the multiple-dose study, mild transient soft stools were observed in six volunteers, one volunteer had mild transient diarrhea, and one volunteer had elevated serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase levels (1.4- and 2.8-fold compared with the upper limits of normal, respectively). There were no other abnormal findings for objective symptoms or laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis.     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Behavioural and neurochemical sensitization of morphine-withdrawn rats to quinpirole

The sensitivity of dopamine D2-like receptors in morphine-withdrawn rats was studied using the selective agonist quinpirole. Morphine was administered twice daily increasing the daily dose from 20 to 50 mg/kg during 7 days. Twenty-four hours after the last morphine administration the rats were given quinpirole (0.01-1 mg/kg) and their behavior was assessed. Withdrawal from repeated morphine treatment enhanced yawning behavior and penile erections induced by small doses (0.01-0.1 mg/kg) as well as the intensity of stereotypy induced by a large dose (1.0 mg/kg) of quinpirole. In the morphine-withdrawn rats the dose of 1 mg/kg of quinpirole caused less yawning than in the control rats, whereas the number of erections induced by this dose was enhanced as compared with the control animals. In the control rats, the striatal and limbic concentrations of dopamine metabolites, 3,4-dihydroxphenylacetic acid (DOPAC), and homovanillic acid (HVA), were not clearly affected by the smallest dose of quinpirole. However, the small dose of quinpirole (0.01 mg/kg) significantly reduced the levels of DOPAC and HVA in the striatum and limbic forebrain of the rats withdrawn from morphine either for 24 or 48 h. These findings indicate that withdrawal from repeated morphine treatment enhances the sensitivity of dopamine D2-like receptors.     

Possibility of partial absorption of nicardipine by routes other than the hepato-portal system after oral administration in rats

The systemic availability of nicardipine after different routes of administration has been examined in rats, with particular attention to differentiating oral absorption from intestinal and hepatic metabolism. The quantities of nicardipine and its metabolite were determined by capillary column gas chromatography. A linear relationship was shown between the hepatic first-pass effect and dose after hepato-portal administration of nicardipine; the hepatic first-pass effect was calculated to be approximately 80%. However, the availability after oral and rectal administration was found to be more than twice that observed after hepato-portal administration. Partial avoidance of the hepatic first-pass effect after oral and rectal administration are estimated to be 37.3% and 35.2%, respectively, assuming that all absorbed molecules pass through the liver. These findings suggest that the absorption of nicardipine after oral administration also occurs by routes other than the hepato-portal system.     

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.