Absorption,pharmacokinetics and excretion of levovirin in rats,dogs and cynomolgus monkeys

The absorption, pharmacokinetics and excretion of levovirin were studied in Sprague-Dawley rats (30 mg/kg) and Beagle dogs (30 mg/kg) following intravenous (iv) and oral administration of [(3)H]levovirin, and in Cynomolgus monkeys following iv and oral administration of [(14)C]levovirin. Oral absorption was 31.3% in rats, 67.3% in dogs and 17.5% in monkeys, and the bioavailability was 29.3% in rats, 51.3% in dogs and 18.4% in monkeys. After iv administration, the elimination half-life (t(1/2)) was 1.47 h in rats, 3.70 h in dogs and 3.50 h in monkeys. The total body clearance was 8.24, 2.96 and 2.58 mL/min per kg, respectively, in rats, dogs and monkeys and the apparent volume of distribution was 0.79, 0.95 and 0.65 L/kg. No metabolite was detected in plasma or urine of rats, dogs or monkeys, indicating negligible metabolism of levovirin in these animals. Excretion of total radioactivity in urine after oral dosing accounted for 15.4% of the administered dose in rats, 49.9% in dogs and 21.4% in monkeys. Biliary excretion did not play a significant role in the elimination of levovirin.     

Metabolism and disposition of amifloxacin in laboratory animals.

Sprague-Dawley rats received [14C]amifloxacin mesylate either orally or intravenously at 20 mg (base equivalent) per kg. Blood radioactivity peaked at 0.5 h after oral administration and was equivalent to 7.54 micrograms/ml for males and 6.73 micrograms/ml for females. After intravenous administration to rats, 52.5% of the dose was recovered in the urine of males and 45.3% in the urine of females within 72 h. The corresponding values after oral administration were 50.8% for males and 37.2% for females. The remainder of the dose was recovered in the feces. After intravenous administration of [14C]amifloxacin mesylate at 10 mg (base equivalent) per kg to female rhesus monkeys, 80.3% of the radioactivity was excreted in the urine at 24 h. The apparent first-order terminal elimination half-life of intact amifloxacin in plasma was 2.3 h; radioactivity in plasma was eliminated more slowly. Male rats excreted 26.2% of the dose in the urine as amifloxacin and 17.8% as the piperazinyl-N-oxide derivative of amifloxacin after intravenous administration. The corresponding amounts for female rats were 29.0% as amifloxacin and 7.8% as the piperazinyl-N-oxide metabolite. Similar excretion profiles were observed after oral administration. After intravenous administration, female monkeys excreted 54.5% of the dose in the urine as amifloxacin, 12.9% as the piperazinyl-N-desmethyl metabolite, and 5.6% as the piperazinyl-N-oxide during the first 12 h. In contrast, there was no evidence of the piperazinyl-N-desmethyl metabolite in rats.     

Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals

BRL 42715 is a novel, highly potent beta-lactamase inhibitor with good activity against a broad range of beta-lactamases, including the class I enzymes of Enterobacter and Citrobacter spp. (K. Coleman, D.R.J. Griffin, J.W.J. Page, and P.A. Upshon, Antimicrob. Agents Chemother. 33:1580-1587, 1989). The pharmacokinetics of BRL 42715 were studied following oral and parenteral administration in mice, rats, rabbits, beagle dogs, and cynomolgus monkeys. The elimination half-life (t1/2) of BRL 42715 following intravenous administration was 7 min in rats, 6.2 min in rabbits, 11 min in dogs, and 18 min in cynomolgus monkeys; and interspecies scaling indicated a t1/2 of 31 min in humans. Urinary recovery was 24 to 43% in the three species studied. A linear relationship was observed between the dose and the theoretical concentration in blood at time zero and between the dose and area under the concentration-time curve following intravenous administration to mice. Extravascular dosing in mice, rats, and dogs resulted in an increase in t1/2, suggesting a depot effect. BRL 42715 was absorbed in mice following an oral dose (bioavailability of 0.2), but was not absorbed in rats, dogs, or cynomolgus monkeys to any significant extent. The binding of BRL 42715 in serum was 27 to 38% in mouse, rat, and dog sera but was somewhat higher (68 to 70%) in primate and human sera. BRL 42715 was not readily hydrolyzed by the renal dehydropeptidase enzymes of any of the five species studied.     

Cephradine: Absorption, Excretion, and Tissue Distribution in Animals of a New Cephalosporin Antibiotic

Metabolic studies were conducted with cephradine administred by the oral, subcutaneous, intravenous, or rectal routes to mice, rats, and dogs. Peak blood levels were usually attained in 30 to 150 min after dosing, depending on the animal species studied. Based on urinary excretion, cephradine appeared to be well absorbed after oral or subcutaneous administration; after rectal doses, cephradine was absorbed poorly. In rats and dogs given oral or intravenous doses of cephradine, about 70 to 100% of the administered dose was recovered during a 24-h collection period. Cephradine was excreted unchanged. After the oral or intravenous administration of [(3)H]cephradine to rats and dogs, respectively, its plasma half-life was about 1 h. After oral administration to rats, cephradine was distributed widely throughout the body tissues, with the greatest concentrations in the kidneys and liver; at 45 min to 6 h postdose, cephradine concentrations in the kidneys and liver were about 8 and 3 times higher, respectively, than those in plasma.     

Pharmacokinetics of a novel quinolone, AT-4140, in animals.

The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1- piperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 micrograms/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h, respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after beta-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9, 8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18.9%, respectively, after beta-glucuronidase treatment. The pharmacokinetics of AT-4140 may be characterized by its good tissue penetration and its long half-life in plasma and tissues.     

Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs.

We studied the pharmacokinetics and metabolism of rimantadine hydrochloride (rimantadine) following single-dose oral and intravenous administration in mice and dogs. Absorption of the compound in mice was rapid. Maximum concentrations in plasma occurred at less than 0.5 h after oral administration, and the elimination half-life was 1.5 h. Peak concentrations in plasma following oral administration were markedly disproportional to the dose (274 ng/ml at 10 mg/kg, but 2,013 ng/ml at 40 mg/kg). The bioavailability after an oral dose of 40 mg/kg was 58.6%. Clearance was 4.3 liters/h per kg, and the volume of distribution was 7.6 liters/kg at 40 mg/kg. In contrast to the results observed in mice, absorption of the compound in dogs was slow. Maximum concentrations in plasma occurred at 1.7 h after oral administration, and the elimination half-life was 3.3 h. A further difference was that peak concentrations in plasma were approximately proportional to the dose. Following administration of a single oral dose of 5, 10, or 20 mg/kg, maximum concentrations in plasma were 275,800, and 1,950 ng/ml, respectively. The bioavailability after an oral dose of 5 mg/kg was 99.4%. The clearance was 3.7 liters/h per kg, and the volume of distribution was 13.8 liters/kg at 5 mg/kg. Mass balance studies in mice, using [methyl-14C]rimantadine, indicated that 98.7% of the administered dose could be recovered in 96 h. Less than 5% of the dose was recovered as the parent drug in dog urine within 48 h. Finally, gas chromatography-mass spectrometry studies, done with mouse plasma, identified the presence of two rimantadine metabolites. These appeared to be ring-substituted isomers of hydroxy-rimantadine.     

Pharmacokinetics of vibunazole (BAY n 7133) administered orally to healthy subjects

The role of gastric acidity in the absorption of the new antifungal drug vibunazole was studied in six healthy volunteers. Vibunazole was administered orally as 400 mg tablets to fasting subjects under three conditions: after 400 mg cimetidine orally, after 30 ml diluted hydrochloric acid orally, and alone. Plasma concentrations of vibunazole were determined with HPLC. The plasma concentration profile of vibunazole could be described adequately by a one-compartmental open model with first-order absorption. Kinetic parameters after oral administration did not differ between the three modes of administration. The mean peak time was 1 h 29 min (after lag-time). The mean peak concentration was 2.76 mg/l. The mean elimination half-life of vibunazole was 2 h 22 min. The mean absorption lag-time was 30 min, with considerable variation.     

Pharmacokinetics of SCH 56592, a new azole broad-spectrum antifungal agent, in mice, rats, rabbits, dogs, and cynomolgus monkeys

SCH 56592 is a new broad-spectrum azole antifungal agent that is in phase 3 clinical trials for the treatment of serious systemic fungal infections. The pharmacokinetics of this drug candidate were evaluated following its intravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropyl-beta-cyclodextrin (HPbetaCD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, and cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. The oral bioavailability was higher with the HPbetaCD solution (range, 52 to approximately 100%) than from the MC suspension (range, 14 to 48%) and was higher in mice ( approximately 100% [HPbetaCD] and 47% [MC]), rats ( approximately 66% [HPbetaCD] and 48% [MC]), and dogs (72% [HPbetaCD] and 37% [MC]) than in monkeys (52% [HPbetaCD] and 14% [MC]). In rabbits, high concentrations in serum suggested good oral bioavailability with the MC suspension. The i.v. terminal-phase half-lives were 7 h in mice and rats, 15 h in dogs, and 23 h in monkeys. In rabbits, the oral half-life was 9 h. In species given increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentrations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weight for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulation index of approximately 2.6. Concentrations above the MICs and minimum fungicidal concentrations for most organisms were observed at 24 h following a single oral dose in MC suspension in all five species studied (20 mg/kg for mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting that once-daily administration of SCH 56592 in human subjects would be a therapeutically effective dosage regimen.     

Energetics of tetracycline transport into Escherichia coli

The pharmacokinetics of Sch 28191, the N-D-ornithyl methyl ester of amphotericin B, and amphotericin B were studied in mice, rats, dogs, and cynomolgus monkeys after an intravenous dose of 0.6 mg/kg was administered. The decline in the concentrations of Sch 28191 and amphotericin B in serum appeared to be biphasic in nature. The half-life at the distribution phase and the half-life at the elimination phase of Sch 28191 were similar to those of amphotericin B in all animals studied. The half-life at the distribution phase in serum was 0.9 to 1.5 h in all animals studied. The half-lives at the elimination phase in serum were 25 to 28 h in mice, 16 to 18 h in rats, 44 to 47 h in dogs, and 35 h in cynomolgus monkeys. The areas under the serum concentration-time curves of Sch 28191 were five- to eightfold larger than those of amphotericin B in rats, dogs, and cynomolgus monkeys but were only slightly larger than those of amphotericin B in mice. In dogs, the urinary excretion (over 9 days) of unchanged drug accounted for 23% of the Sch 28191 dose and 25% of the amphotericin B dose. The concentrations of Sch 28191 in serum were also studied after the intravenous administration of 0.3, 0.6, or 1.25 mg/kg to dogs. The serum concentration-time curves were parallel for these doses. There was a linear relationship between the areas under the concentration-time curves and the doses, indicating dose proportionality.     

Pharmacokinetics and metabolism of [(14)C]ribavirin in rats and cynomolgus monkeys

Absorption, pharmacokinetics, distribution, metabolism, and excretion of [(14)C]ribavirin were studied in rats (30 mg/kg of body weight) and cynomolgus monkeys (10 mg/kg) after intravenous (i.v.) and oral administration. The oral absorption and bioavailability were 83 and 59%, respectively, in rats and 87 and 55%, respectively, in monkeys. After i.v. administration, the elimination half-life (t([1/2])) was 9.9 h in rats and 130 h in monkeys and the total body clearance was 2,600 ml/h/kg in rats and 224 ml/h/kg in monkeys. The apparent volume of distribution was 11.4 liter/kg in rats and 29.4 liter/kg in monkeys. There was extensive distribution of drug-derived radioactivity into red blood cells and extensive metabolism of ribavirin in rats and a lesser degree of metabolism in monkeys. Excretion of total radioactivity in urine from rats accounted for 84% of the i.v. dose and 83% of the oral dose, whereas that from monkeys accounted for 47% of the i.v. dose and 67% of the oral dose. Several metabolites were observed in plasma and urine from both species. The amount of unchanged ribavirin in urine from both species was quite small after either i.v. or oral administration.     

Pharmacokinetics of the cephalosporin SM-1652 in mice, rats, rabbits, dogs, and rhesus monkeys.

The pharmacokinetics of SM-1652 were studied in mice, rats, rabbits, dogs, and rhesus monkeys. The plasma half-lives of SM-1652, administered intravenously at a dose of 20 mg/kg, were 11.0 min in mice, 26.0 min in rats, 65.8 min in rabbits, 72.6 min in dogs, and 150.9 min in monkeys. The 24-h urinary excretion of SM-1652 was 30 to 35% of the dose in mice and rats, 70 to 75% in rabbits and dogs, and 45% in monkeys. Biliary excretion of the antibiotic over a 24-h period was 60 and 19% in rats and rabbits, respectively; it was 19% in dogs over a 9-h period after SM-1652 administration. Approximately 95% of the intravenous dose of SM-1652 was recovered as the unchanged form in the urine and bile of rats and rabbits. The binding of SM-1652 to serum protein was 44.0% in mice, 46.0% in rats, 90.4% in rabbits, 93.2% in monkeys, 30.0% in dogs, and 96.3% in humans.     

Pharmacokinetic studies of norfloxacin in laboratory animals

Pharmacokinetic studies were conducted with norfloxacin administered by the oral and subcutaneous routes to mice and rats, and by the oral route to rhesus monkeys. The compound was moderately well absorbed following oral dosing in these animal species. Serum levels in monkeys ranged from 1.0 to 2.35 micrograms/ml after an oral drug dose of 25 mg/kg of animal body weight and were similar to those in mice. Serum half-life of norfloxacin in rodents and monkeys was similar to that in humans. Concentrations of norfloxacin in tissues of mice, rats and monkeys were greater than those in serum suggesting a large volume of distribution for the drug.     

Comparative pharmacokinetics of SCE-2787 and related antibiotics in experimental animals.

The pharmacokinetic properties of SCE-2787 administered intravenously at a dose of 20 mg/kg of body weight were studied with mice, rats, rabbits, dogs, and monkeys and were compared with those of ceftazidime, cefpirome, and cefclidin in mice and dogs. The area under the concentration-time curve for plasma after intravenous administration was the largest in monkeys, followed by those in dogs, rabbits, rats, and mice, in that order. The elimination half-life ranged from 0.2 to 0.3 h in mice and rats to 0.7 to 1.3 h in rabbits, dogs, and monkeys. In young dogs, the concentrations of SCE-2787 in plasma were somewhat lower than those in the mature dogs. SCE-2787 was distributed well to the tissues, and the highest concentration was found in the kidneys in all species tested; the distribution to the lungs, liver, and spleen was also good, but the concentrations in these tissues were lower than those in the plasma. The pharmacokinetic parameters and urinary excretion of SCE-2787 in mice and dogs were similar to those of ceftazidime, cefpirome, and cefclidin. The maximum concentrations in the cerebrospinal fluid of rats and rabbits were 0.8 and 1.3 micrograms/ml, and the relative percentages of the area under the concentration-time curve of SCE-2787 in the cerebrospinal fluid to that in the plasma were 4.6 and 6.4%, respectively. SCE-2787 was excreted mainly in the urine; the recovery rate ranged from 74% (rats) to 90% (dogs) of the dose. The biliary excretion of SCE-2787, however, was low, amounting to about 1.4% for mice and rats and less than 0.5% for rabbits and dogs. In rats, there was no accumulation in the tissues and no delay in urinary excretion upon multiple intravenous administration of 20 mg of SCE-2787 per kg once daily for 7 days. No active metabolites were found in the plasma or urine of animals given SCE-2787. The binding of SCE-2787 to serum protein in mice, rats, dogs, monkeys, and humans was less than 11% and similar to that of cefclidin.     

Disposition of arildone, an antiviral agent, after various routes of administration.

[14C]arildone was administered both topically and intravaginally to mice 5 times a day for 7 days to simulate conditions of clinical usage. Urinary and fecal excretion of radioactivity indicated that arildone was extensively absorbed by both routes of administration. The levels of radioactivity in the vagina and skin declined from about 12 micrograms equivalents per g to 3 micrograms equivalents per g between 1 and 2 days after the last application. Only small amounts of unchanged arildone were found in urine from the vaginally treated animals; the major urinary metabolites were chloromethoxyphenol, its sulfate ester, and chlorohydroquinone sulfate. After about 1 month of daily oral administration of arildone to rats and monkeys or vaginal administration three times a day for 20 days to dogs, only low levels of intact drug were found in the systemic circulation. The disposition or beta-phase half-life of arildone in monkeys after intravenous administration was about 0.5 h. The disposition of [14C]arildone in mice, rats, dogs, and monkeys after various routes of administration was also investigated.     

Absorption, distribution, metabolic fate, and elimination of pefloxacin mesylate in mice, rats, dogs, monkeys, and humans

Pefloxacin mesylate is well absorbed by the oral route. The antimicrobial activity in dog, cynomolgus monkey, and human plasma was essentially due to unchanged drug which respectively accounted for 64, 94, and 84% of the total activity (ratios derived from relative area under the curve [AUC] values). Half-lives ranged from 1.9 h in mice to 8.6 h in humans. Protein binding was weak, about 20% in plasma. Except in brain, concentrations in most of the organs and tissues tested in rats and dogs were higher than the plasma levels. Microbiological activity in urine was mainly due to pefloxacin and norfloxacin, the N-desmethyl metabolite. The norfloxacin/pefloxacin ratios were 0 in mice, ca. 1 in rats and dogs, 1.6 in cynomolgus monkeys, and 2.3 in humans. The principal urinary compounds were unchanged drug in mice, pefloxacin glucuronide and pefloxacin N-oxide in rats and dogs, norfloxacin and pefloxacin in monkeys, and pefloxacin N-oxide and norfloxacin in humans. The urinary recovery of identified metabolites was 29.5% of the dose in mice, 37.8% in rats, 36.3% in dogs, 26.5% in monkeys, and 58.9% in humans. Biliary excretion occurred and was extensive in rats and dogs, mainly as a glucuronide conjugate of the drug. In rat and human bile, the main active compound was unchanged pefloxacin.     

Pharmacokinetic studies of CP-74,667, a new quinolone, in laboratory animals.

The pharmacokinetics of CP-74,667 (7-(8'-methyl-3',8'-diazabicyclo[3.2.1]oct-3'-yl)-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) were studied following oral or parenteral administration in mice, rats, rabbits, dogs, and cynomolgus monkeys. The mean peak levels of CP-74,667 in serum following a single oral dose of 20 mg/kg of body weight were similar in all species, with a range of 3.7 micrograms/ml in mice to 5.6 micrograms/ml in dogs. In contrast, elimination half-lives were species dependent, with mean values of 2.1, 1.8, 4.5, 7.8, and 13.1 h in mice, rats, rabbits, dogs, and monkeys, respectively. The oral bioavailability of CP-74,667 was 100% in dogs and monkeys, as determined by intravenous-oral crossover experiments. The maximum concentration of drug in serum and area under the concentration-time curve (AUC) of CP-74,667 in dogs were proportional to dose over the range of 5 to 40 mg/kg. Accumulation of drug in serum was observed following the administration of four once-a-day doses of 7.1 mg/kg in monkeys (mimicking a 500-mg human dose), with significant increases in half-life, maximum and minimum concentrations of drug in serum, and AUC. The good tissue penetration of CP-74,667 suggested by a volume of distribution in excess of 2 liters/kg in dogs and monkeys was confirmed by tissue distribution studies with the same species, which demonstrated tissue concentrations (except for those in brain tissue) greater than 1.45 times higher than corresponding levels in serum. The mean urinary recoveries of unchanged drug were 17.7% in rats, 7.8% in monkeys, and 4.9% in dogs. Metabolism studies in dogs, following intravenous dosing, indicated that renal excretion of CP-74,667-related materials accounted for 41.6% of the administered dose, while biliary recoveries accounted for 6.8%. The CP-74,667 N-oxide metabolite was the primary drug-related material eliminated via renal excretion (37.2% of dose). The pharmacokinetics of CP-74,667 describe a quinolone with complete oral absorption, linear pharmacokinetics, a long elimination half-life, and wide distribution into tissues.     

Comparative Pharmacokinetics of BB-K8 and Kanamycin in Dogs and Humans

Comparative studies in beagle dogs suggested that the pharmacokinetic profiles of BB-K8 and kanamycin are similar. After intravenous (iv) administration to dogs, BB-K8 and kanamycin were rapidly distributed in plasma and tissue fluids; their "apparent" volumes of distribution comprised approximately 23% of the total body volume. Like kanamycin, BB-K8 had a plasma half-life of about 0.8 h which paralleled the urinary excretion rate. Approximately 92% of the dose was excreted as unchanged drug within 6 h of dosing, and clearance appeared to be primarily by glomerular filtration. After intramuscular (im) administration to dogs, BB-K8 and kanamycin were totally and rapidly absorbed; peak concentrations in the plasma occurred 0.5 to 1.0 h after dosing. The kinetic parameters governing the distribution and elimination of BB-K8 and kanamycin after an im dose were similar to those obtained for iv dosing and indicate desirable dose-independent kinetics. A human pharmacokinetic study indicated that the kinetic profiles of BB-K8 and kanamycin are similar in man after im dosing. Like kanamycin, BB-K8 is rapidly absorbed, yielding peak serum concentrations of about 20 mug/ml at 1 h after a 500-mg im dose. The plasma half-life of these two drugs was approximately 2.3 h. Clearance in man was primarily by glomerular filtration, and the urinary excretion of BB-K8 and kanamycin accounted for 83% of the dose.     

Pharmacokinetics of new broad-spectrum cephamycin, YM09330, parenterally administered to various experimental animals.

The pharmacokinetics of YM09330, a new semisynthetic cephamycin, were determined after intravenous and intramuscular administration to experimental animals. Mean plasma levels of YM09330 at 30 min after intravenous administration of 20 mg/kg were 5.5 micrograms/ml for mice, 17 micrograms/ml for rats, 24 micrograms/ml for rabbits, 42 micrograms/ml for dogs, and 76 micrograms/ml for monkeys; plasma half-lives were 13.0, 15.9, 30.5, 55.5, and 75.6 min, respectively. The half-lives of YM09330 were longer than those of cefmetazole in all species tested. In monkeys, plasma levels of YM09330 were higher and more prolonged than those of cefazolin. In rats and dogs, the concentrations of YM09330 were highest in the kidneys, followed by the liver, plasma, lung, spleen, and heart in that order; they were similar to those of cefazolin in rats. Urinary excretion of YM09330 within 48 h of intravenous administrations was 67% of the dose in mice, 52% in rats, 74% in rabbits, 53% in dogs, and 60% in monkeys. In rats, 48% of the dose of YM09330 was detected in the plasma, urine, or bile. However, small amounts of an antibacterially active tautomer of YM09330 were recovered in the urine of mice, rats, and dogs, whereas large amounts of the tautomer were recovered in the urine of rabbits and monkeys. Serum protein binding of YM09330 was 30% of rats, 51% for rabbits, 39% for dogs, 87% for monkeys, and 91% for humans.     

Pharmacokinetics and disposition of CS-023 (RO4908463), a novel parenteral carbapenem, in animals

The distribution, metabolism, and excretion of CS-023 (RO4908463), a new carbapenem, were investigated in rats and monkeys after a single intravenous administration of [(14)C]CS-023. In addition, the drug's pharmacokinetics were examined in rats, dogs, and monkeys. Whole-body autoradioluminograms of rats indicated that the radioactivity is distributed throughout the body immediately after administration except for the central nervous system and testes. The highest radioactivity was found in the kidneys, which are responsible for the excretion of CS-023. R-131624 with an open beta-lactam ring, the pharmacologically inactive form, was detected in the plasma and urine as the major metabolite. In rat plasma, the R-131624 levels became higher than CS-023 levels at 30 min postdose and thereafter, while in monkey plasma, CS-023 accounted for most of the radioactivity, with low levels of R-131624. More than 80% of the radioactivity administered was recovered in the urine, and CS-023 and R-131624 accounted for 29.6% and 31.4%, respectively, of the dose in rats and 51.2% and 18.5%, respectively, of the dose in monkeys. The faster metabolism to R-131624 in rats than in monkeys was likely due to the metabolism by dehydropeptidase I in rat lungs. The plasma elimination half-life of CS-023 was 0.16 h in rats, 0.75 h in dogs, and 1.4 h in monkeys. There were no appreciable interspecies differences among the animals tested in either volume of distribution (172 to 259 ml/kg) or serum protein binding (5.0 to 15.6%). The total clearance in monkeys (1.62 ml/min/kg) was lower than that in rats (15.1 ml/min/kg) or dogs (4.19 ml/min/kg).     

Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease.

AG1343, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease (Ki = 2 nM), was designed by protein structure-based drug design techniques. AG1343 has potent antiviral activity (95% effective dose = 0.04 microgram/ml) against a number of HIV-1 strains in acute and chronic models of infection. As part of its preclinical development, the oral bioavailability of AG1343 in rats, dogs, monkeys, and marmosets was determined and its tissue distribution in rats was evaluated. There were no major interspecies differences in AG1343 pharmacokinetics. Following intravenous administration, the elimination half-life of AG1343 ranged from 1 to 1.4 hr. The total volume of distribution (2 to 7 liters/kg) exceeded the volume of total body water, indicating extensive tissue distribution. Systemic clearance of AG1343 (1 to 4 liters/kg) in the different species corresponded to hepatic blood flow, suggesting possible hepatic involvement in the elimination of AG1343. Following oral administration, peak levels in plasma ranged from 0.34 microgram/ml after treatment with 10 mg/kg of body weight in the dog to 1.7 micrograms/ml after dosing with 50 mg/kg in the rat. Because of the slow absorption of AG1343, plasma concentrations of AG1343 exceeding that required for 95% inhibition of HIV-1 replication were maintained for up to 7 h after a single oral dose in all species evaluated. Average oral bioavailability of AG1343 ranged from 17% in the marmoset to 47% in the dog. Studies of distribution to tissue in the rat after oral administration of 14C-AG1343 established extensive distribution with concentrations in most tissues exceeding that found in plasma. Of particular significance were high levels of AG1343 equivalent in mesenteric lymph nodes (32.05 micrograms/g) and spleen tissue (9.33 micrograms/g). The major excretory route for AG1343 was via feces, with 100% of the dose recovered by 48 h. Results from these studies demonstrate that AG1343 is orally bioavailable and that levels in plasma in the therapeutic range are achievable and are maintained for prolonged periods in the animal models tested. On the basis of these and other findings, AG1343 was developed for further testing in human subjects.