Effects of acute renal failure on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats.

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). After intravenous administration in rats with U-ARF, the time-averaged total body clearance (Cl) was significantly faster (2.45 versus 0.932 ml/min/kg) than controls due to significantly faster nonrenal clearance (2.25 versus 0.855 ml/min/kg) in rats with U-ARF. The faster nonrenal clearance could be due to significantly greater gastrointestinal (including biliary) excretion; the amount of unchanged DA-7867 recovered from the entire gastrointestinal tract at 24 h was significantly greater (30.3% versus 9.38% of intravenous dose) in rats with U-ARF. In rats with U-ARF, the Vss was significantly larger (1420 ml/kg compared with 580 ml/kg), but this was not due to a difference in plasma protein binding; the values were comparable between the two groups of rats. After oral administration to rats with U-ARF, the total area under the plasma concentration-time from time zero to time infinity (AUC) of DA-7867 was significantly smaller than the controls (2560 microg min/ml versus 7440 microg min/ml), and this was not due mainly to a decrease in absorption from the gastrointestinal tract in rats with U-ARF.

Effects of omeprazole or cola beverage on the pharmacokinetics of oral DA-8159, a new erectogenic, in rats.

The changes in pharmacokinetics of DA-8159 by omeprazole with respect to inhibition of CYP3A1/2 in rats were evaluated. After oral administration of DA-8159 at dose of 30 mg/kg to rats pretreated with oral omeprazole at 30 mg/kg for 1 week, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 was significantly greater (37.5% increase) than that in control rats. This could be due to inhibition of metabolism of DA-8159 by inhibition of CYP3A1/2 by omeprazole. The AUC(DA-8164 (a metabolite of DA-8159))/AUC(DA-8159) ratio was also smaller (32.4% decrease) with omeprazole. After oral administration of DA-8159 at a dose of 30 mg/kg to rats without or with cola beverage, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between two groups of rats. This suggested that cola beverage did not have any considerable effects on CYP3A1/2 in rats.

Pharmacokinetic changes of DA-8159, a new erectogenic, and one of its metabolites, DA-8164 after intravenous and oral administration of DA-8159 to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats.

The pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to spontaneously hypertensive rats (SHRs) at 16 and 6 weeks old and their respective age-matched control normotensive Kyoto-Wistar rats (KW rats), and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) at 16 weeks old and their age-matched control Sprague-Dawley rats. After oral administration of DA-8159 to 16-week-old SHRs, the AUC values of both DA-8159 (157 versus 103 microg min/ml) and DA-8164 (215 versus 141 microg min/ml) were significantly greater, but the values of DA-8159 were reversed in 16-week-old DOCA-salt rats (125 versus 200 microg min/ml). However, the AUC values of both DA-8159 and DA-8164 were not significantly different between the 6-week-old SHRs and their control rats. The above AUC differences in 16-week-old SHRs may be due to neither hereditary characteristics of SHRs nor the hypertensive state itself.

Interspecies pharmacokinetic scaling of DA-8159, a new erectogenic, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics.

Time-averaged total body clearance (Cl) and apparent volume of distribution at steady state (V(SS)) of DA-8159 after intravenous administration to mice (30 mg/kg), rats (30 mg/kg), rabbits (30 mg/kg) and dogs (3 mg/kg) were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict those in humans. Significant linear relationships were obtained between log Cl (l/h) and log W (kg) (r = 0.992; p = 0.0079) and log V(SS) (l) and log W (kg) (r = 0.999; p < 0.0001). The corresponding allometric equations were Cl = 4.36 W(0.492) and V(SS) = 6.41 W(0.911). These allometric equations were extrapolated to predict the Cl and V(SS) for DA-8159 in humans based on the 70 kg body weights. In addition, concentrations in the plasma-time profile predicted using the four animal data fitted to a complex Dedrick plot of animal data. Our results indicated that the DA-8159 data obtained from four laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous DA-8159, a new erectogenic, in rats.

In order to find what types of hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of DA-8159 and in the formation of DA-8164 in rats, enzyme inducers, such as dexamethasone, phenobarbital, 3-methylcholanthrene and isoniazid, and enzyme inhibitors, such as troleandomycin and quinine, were pretreated in rats. After a 1 min intravenous administration of DA-8159 at a dose of 30 mg/kg to rats pretreated with dexamethasone (a main inducer of CYP3A1/2 in rats), the total areas under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8159 (283 versus 349 microg min/ml) and DA-8164 (98.0 versus 79.8 microg min/ml) were significantly smaller and greater, respectively, than those in control rats. However, the AUC values of DA-8159 were not significantly different after pretreatment with phenobarbital, isoniazid and 3-methylcholanthrene (main inducers of CYP2B1/2, 2E1 and 1A1/2, respectively, in rats). In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC values of DA-8159 (435 versus 370 microg min/ml) and DA-8164 (34.8 versus 76.5 microg min/ml) were significantly greater and smaller, respectively. However, in rats pretreated with quinine (a main inhibitor of CYP2D1 in rats), the AUC of DA-8159 was comparable to that in control rats. The above data indicate that DA-8159 was metabolized and DA-8164 was formed mainly via CYP3A1/2 in rats.

Pharmacokinetic changes of DA-7867, a new oxazolidinone, after intravenous and oral administration to rats with short-term and long-term diabetes mellitus induced by streptozotocin.

Effects of diabetes mellitus induced by streptozotocin (DMIS) on the pharmacokinetics of DA-7867 were investigated after i.v. and oral administration (10mg/kg) to control Sprague-Dawley rats and DMIS rats (at 7th and 29th days after administration of streptozotocin, 45mg/kg). After i.v. administration to DMIS rats, the AUC(0-infinity) values were significantly smaller (50.7 and 64.8% decrease for 7th and 29th days, respectively); this could be due to significantly faster Cl values in the rats (127 and 183% increase for 7th and 29th days, respectively). The faster Cl values were mainly due to significantly greater amount of unchanged drug excreted in 24-h urine (Ae(0-24h)). The greater Ae(0-24h) in DMIS rats could be due to urine flow rate-dependent renal clearance of DA-7867. After oral administration to DMIS rats, the AUC(0-infinity) values were also significantly smaller (61.3 and 72.6% decrease for 7th and 29th days, respectively); this could also be mainly due to significantly greater Ae(0-24h) in the rats. Streptozotocin-induced hepatotoxicity did not influence considerably on the pharmacokinetics of DA-7867 at 7th day when compared with those at 29th day.

Pharmacokinetics of DA-8159, a new erectogenic, administered at 10:00 h versus 22:00 h in rats.

Little is known about chronopharmacokinetics of PDE V inhibitors in rats as well as in humans. Hence, the pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were investigated after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg administered at 10:00 h versus 22:00 h in rats. After intravenous administration of DA-8159 at 22:00 h, the AUC of DA-8159 was significantly greater (528 versus 368 microg min/ml) due to significantly slower CL (56.1 versus 79.5 ml/min/kg) in the rats. After intravenous administration of DA-8159 at 22:00 h, the AUC of DA-8164 was also significantly greater (108 versus 66.8 microg min/ml) possibly due to significantly greater exposure of the parent drug (AUC of DA-8159). After intravenous administration of DA-8164 at 22:00 h, the CL of DA-8164 was significantly slower; hence, this factor could also contribute to the greater AUC of DA-8164 after intravenous administration of DA-8159. However, after oral administration of DA-8159, the AUC values of both DA-8159 and DA-8164 were not significantly different between 10:00 h and 22:00 h. This was not due to decrease in gastrointestinal absorption of DA-8159 at 22:00 h and may be due to changes in intestinal first-pass effect at 22:00 h. The above data suggested that modification of dosage regimen of oral DA-8159 is not necessary in humans between 10:00 h and 22:00 h. Further studies are needed in humans.

Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159, a new erectogenic, to mice, rats, rabbits, dogs and humans.

Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159 to mice, rats, rabbits, dogs and humans were investigated. After intravenous administration of DA-8159, the formation of DA-8164 decreased in the order mice, rats, rabbits and dogs; the AUC(DA-8164)/AUC(DA-8159) ratios were 0.479, 0.199, 0.0452 and close to 0 (DA-8164 was below the detection limit in dog plasma), respectively. After oral administration of DA-8159, the formation of DA-8164 was considerable in mice, rats and humans, but almost negligible in dogs; the AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios were 2.99, 2.67, 1.39 and 0.0650, respectively. The above data suggested that the formation of DA-8164 was almost negligible after both intravenous and oral administration in dogs. The species differences for the formation of DA-8164 may be due to the involvement of different CYP isozymes for each species and/or a different amount or activity of CYP isozyme if the same CYP isozyme is involved for the formation of DA-8164 for all species. The AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios after oral administration were greater than those after intravenous administration in mice, rats and dogs, and this could be due to considerable first-pass (gastric, intestinal and/or hepatic) effects in the species as proved in rats.

Dose-independent pharmacokinetics of torasemide after intravenous and oral administration to rats.

After intravenous (at doses of 1, 2, 5, and 10 mg/kg) and oral (at doses of 1, 5, and 10 mg/kg) administration of torasemide, the pharmacokinetic parameters were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses; the values were 95.6, 98.8, and 97.3% for oral doses of 1, 5, and 10 mg/kg, respectively. The high F values indicated that the first-pass (gastric, intestinal, and hepatic) effects of torasemide in rats could be almost negligible. After intravenous administration, the total body clearances of torasemide were extensively slower than the reported cardiac output in rats and hepatic extraction ratio was only 3-4% suggesting almost negligible first-pass effects of torasemide in the heart, lung, and liver in rats. Based on in vitro rat tissue homogenate studies, the tissues studied also showed negligible metabolic activities for torasemide. Equilibrium of torasemide between plasma and blood cells of rat blood reached fast and plasma-to-blood cells concentration ratio was independent of initial blood concentrations of torasemide, 1, 5, and 10 microg/ml; the mean value was 0.279. Protein binding of torasemide to fresh rat plasma was 93.9 +/- 1.53% using an equilibrium dialysis technique.

Effects of bacterial lipopolysaccharide on the pharmacokinetics of DA-8159, a new erectogenic, in rats.

Pharmacokinetic parameters of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to control rats and rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). After intravenous and oral administration of DA-8159, most of the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between two groups of rats. This suggested that the pharmacokinetic parameters of DA-8159 and DA-8164 were not affected considerably by KPLPS.

Excretion and metabolism of DA-7867, a new oxazolidinone, in rats.

Almost negligible hepatic metabolism (minor role of liver for the metabolism) and extensive urinary and fecal excretion of DA-7867 were investigated after intravenous administration at a dose of 10 mg/kg to rats. Pharmacokinetic parameters, especially nonrenal clearances of DA-7867, were very similar between control rats and rats pretreated with SKF 525-A, a nonspecific inhibitor of CYP isozymes, in rats. Similar results were also obtained between control rats and rats with liver cirrhosis induced by dimethylnitrosamine. Hepatic first-pass effect of DA-7867 was almost negligible in rats; the areas under the plasma concentration-time curve from time zero to time infinity of DA-7867 were not significantly different between intravenous and intraportal administration. The above data indicated that liver had almost negligible metabolic activity for DA-7867 in rats. Since metabolism of DA-7867 was not considerable in rats, urinary and fecal excretion of the drug was measured for up to 14 days in ten rats. Fecal excretion was the major route for elimination of DA-7867 in rats; approximately 85.0% of intravenous dose of DA-7867 at 10 mg/kg was recovered from urine (17.0% of intravenous dose), feces (64.0% of intravenous dose), washings of the metabolic cage (3.16% of intravenous dose), and entire gastrointestinal tract (0.421% of intravenous dose).

Pharmacokinetics of intravenous and oral DA-8159, a new erectogenic, in rats with protein-calorie malnutrition.

Influence of dietary protein deficiency on the pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, was investigated after intravenous and oral administration of DA-8159 at a dose of 30 mg kg(-1) to male Sprague-Dawley rats allowed free access to a 23% (control) or 5% (protein-calorie malnutrition, PCM) casein diet for 4 weeks. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8164 were significantly smaller after both intravenous (87.0 vs 162 microg min mL(-1)) and oral (144 vs 319 microg min mL(-1)) administration of DA-8159 to PCM rats. This could be due to the decrease in CYP3A1/2 (50-60%) in the rats because DA-8164 was mainly formed via CYP3A1/2 in rats. This could be supported by significantly slower in-vitro CL(int) (2.04+/-0.646 vs 3.15+/-0.693 microL min(-1) (mg protein)(-1)) for the formation of DA-8164 in hepatic microsomal fraction of PCM rats. After intravenous administration of DA-8159, the AUC values of DA-8159 were not significantly different between the two groups of rats although the AUC of DA-8164 was significantly smaller in PCM rats, and this may be due to the minor metabolic pathway of DA-8164 in rats. However, after oral administration of DA-8159, the AUC of DA-8159 was significantly greater in PCM rats (194 vs 122 microg min mL(-1)). This was not due to enhanced absorption of DA-8159 from the gastrointestinal tract in the rats but may be due to a decreased intestinal first-pass effect of DA-8159 in the rats.

Pharmacokinetics of clarithromycin in rats with acute renal failure induced by uranyl nitrate.

In rats pretreated with dexamethasone (an inducer of CYP3A1/2 in rats) and troleandomycin (an inhibitor of CYP3A1/2 in rats), the area under the plasma concentration-time curve from time zero to time infinity (AUC) values of clarithromycin were significantly smaller (365 compared with 600 micro g min/ml) and greater (1410 compared with 581 micro g min/ml), respectively, than those in control rats. This indicated that clarithromycin was metabolized via CYP3A1/2 in rats. The expression of CYP3A1(23) increased in rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). Hence, it could be expected that AUC of clarithromycin could be smaller in rats with U-ARF. However, after intravenous administration of clarithromycin at a dose of 20mg/kg, the AUC and time-averaged total body (Cl) and nonrenal (Cl(nr)) clearance values were comparable between the two groups of rats. The 9000 x g supernatant fraction of liver homogenates in rats with U-ARF had comparable metabolic activities for clarithromycin compared with those in control rats, suggesting that the CYP3A isozyme responsible for metabolism of clarithromycin seemed not to be expressed considerably in the rats. This could explain the comparable AUC, Cl and Cl(nr) values of clarithromycin between the two groups of rats.

Effects of bacterial lipopolysaccharide on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats.

Pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg to control rats and rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). After intravenous administration of DA-7867 at a dose of 10 mg/kg to 10 rats, metabolism of DA-7867 was minimal; however, the urinary and gastrointestinal excretion of DA-7867 were approximately 85% of intravenous dose when collected for up to 14 days. After intravenous administration to rats pretreated with KPLPS, the AUC was significantly greater (14,100 versus 9810 microg x min/mL), and this could be due to significantly slower total body clearance (CL, 0.709 versus 1.02 mL/min/kg). The slower CL in the rats could be due to significantly smaller fecal excretion of DA-7867 for up to 14 days (41.1 versus 58.8% of intravenous dose of DA-7867) because urinary excretion of DA-7867 was not significantly different between two groups of rats. After oral administration, the AUC values were not significantly different between two groups of rats and this was mainly due to decrease in absorption from the gastrointestinal tract in rats pretreated with the KPLPS (approximately 82 and 95% of oral dose were absorbed for rats with KPLPS and control rats, respectively).

Pharmacokinetic changes of DA-8159, a new erectogenic, after intravenous and oral administration to rats with diabetes mellitus induced by streptozotocin.

Intravenous administration of DA-8159, 30 mg/kg, to rats with diabetes mellitus induced by streptozotocin (DMIS), AUC of DA-8164 (a metabolite) was significantly smaller in rats with DMIS (57.9 compared with 81.8 microg x min/mL). This may be due to more contribution of significantly faster clearance of DA-8164 than that of significantly greater formation of DA-8164 in the rats. For example, the CL of DA-8164 was significantly faster (9.68 compared with 6.29 mL/min/kg) after intravenous administration of DA-8164, 10 mg/kg, to rats with DMIS and in vitro intrinsic clearance for the formation of DA-8164 was significantly faster (1.92 compared with 1.59 microL/min/mg protein) in hepatic microsomal fraction of rats with DMIS due to significant increase in expression of CYP3A1(23) in the rats. DA-8164 was formed mainly via CYP3A1/2 in rats. After intravenous administration of DA-8159, renal clearance was significantly faster in rats with DMIS (5.79 compared with 2.80 mL/min/kg) due to urine flow-dependent renal clearance of DA-8159 in rats. After oral administration of DA-8159, the AUC values of both DA-8159 and DA-8164 were not significantly different between two groups of rats. Although the exact reason is not known it may be due to changes in first-pass effect of DA-8159 in rats with DMIS.

Pharmacokinetics, blood partition and protein binding of DA-7867, a new oxazolidinone.

The pharmacokinetics after single intravenous and single and consecutive 2 week oral administration, tissue distribution, in vitro tissue metabolism, stability, blood partition and protein binding of DA-7867, a new oxazolidinone, were evaluated. After intravenous administration at a dose of 10mg/kg to rats, DA-7867 was eliminated slowly with time-averaged total body clearance of 0.915 ml/min/kg. After consecutive 2 week oral administration at a dose of 2 mg/kg/day to rats, DA-7867 was accumulated in rats; the AUC was significantly greater (1430 versus 1880 micro g min/ml) than that after single oral administration at a dose of 2 mg/kg. The rat tissues studied had low affinity to DA-7867; the tissue-to-plasma ratios were smaller than unity after both intravenous and oral administration at a dose of 20 mg/kg. The rat tissues studied had almost negligible metabolic activity for DA-7867 based on 30 min incubation of DA-7867 with 9000 g supernatant fraction of rat tissues. DA-7867 was stable for up to 24 h incubation in various buffer solutions having pHs from 1 to 11, Sørensen phosphate buffer of pH 7.4, and rat plasma, urine and liver homogenate and 3h incubation in five human gastric juices. The binding of DA-7867 to 4% human serum albumin was 50.6% at DA-7867 concentrations ranging from 0.5 to 20 micro g/ml. The equilibrium of DA-7867 between plasma and blood cells of rabbit blood reached fast (within 30 s manual mixing), and the plasma-to-blood cell concentration ratios were independent of initial blood concentrations of DA-7867, 1-20 micro g/ml; the values ranged from 1.39 to 1.63. Protein binding of DA-7867 in five fresh rats plasma was 72.3%.

Pharmacokinetic changes of DA-8159, a new erectogenic, after intravenous and oral administration to rats with acute renal failure induced by uranyl nitrate.

The pharmacokinetic parameters of DA-8159, a new erectogenic, were compared after intravenous and oral administration of the drug at a dose of 30 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (U-ARF). After intravenous administration to rats with U-ARF, the plasma concentrations of DA-8159 were higher than those in control rats. This resulted in a significantly greater area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 in rats with U-ARF (304 compared with 365 microg min/ml for control rats and rats with U-ARF). The significantly greater AUC in rats with U-ARF was due to significantly slower total body clearance (Cl) of DA-8159 (98.6 compared with 82.2 ml/min/kg). The significantly slower Cl in rats with U-ARF was due to slower renal clearance (1.07 ml/min/kg compared with not calculable, due to impaired kidney function) and nonrenal clearance (97.5 compared with 82.2 ml/min/kg due to slower metabolism) than those in control rats. After oral administration of DA-8159 to rats with U-ARF, the AUC (122 compared with 172 microg min/ml) was significantly greater and Cl(R) was slower (3.47 ml/min/kg compared with not calculable) than those in control rats. The significantly greater AUC in rats with U-ARF could be due to slower Cl of DA-8159 in the rats.

Pharmacokinetics of DA-7867, a new oxazolidinone, after intravenous or oral administration to rats: intestinal first-pass effect.

Pharmacokinetic parameters of DA-7867 were dose independent after both intravenous administration and oral administration (at doses of 1 to 20 mg/kg of body weight) to rats. After oral administration of DA-7867 to rats at a dose of 10 mg/kg, approximately 8.27% of oral dose was not absorbed from the gastrointestinal tract, F was 70.8%, and approximately 21.8% of the oral dose was eliminated by the intestine (intestinal first-pass effect).

Subacute toxicities and toxicokinetics of DA-8159, a new phosphodiesterase type V inhibitor, after single and 4-week repeated oral administration in rats.

The subacute toxicities (10 male and 10 female rats at each dose) and the toxicokinetics (5 male rats at each dose) of DA-8159, a new phosphodiesterase type V (PDE V) inhibitor, were evaluated after single (at day 1) and 4-week (at day 28) oral administration of the drug at doses of 0 (to serve as a control), 20, 80 and 320 mg/kg/day to rats. DA-8159 showed a decrease in body weight gain, clinical signs such as chromodacryohaemorrhoea, ptosis and decreased locomotor activity, an increase in WBC number, changes in parameters related to RBCs, an increase in organ weight of the liver, spleen and lung, and finally microscopic lesions such as cholangiofibrosis and inflammatory cell infiltration in the liver, alveolar macrophage accumulation, and inflammatory cell infiltration in the lung, an increase in bone marrow density and extrahaematopoiesis in the spleen. These changes were observed mainly at a dose of 80 mg/kg or above. While some changes were observed at a dose of 20 mg/kg, these changes were non-specific and transient since this were also observed in control rats. In addition, there was no dose-dependency in these changes. Based on these results, the NOAEL (No-Observed-Adverse-Effect-Level) for DA-8159 in rats was estimated to be 20 mg/kg/day, and the target organs were determined to be liver, bone marrow, spleen, lung and blood cells. After a 4-week oral administration, accumulation of DA-8159 was evident at a dose of 20 mg/kg/day, but was not considerable at toxic doses (80 and 320 mg/kg/day). After a single oral administration, the dose-normalized area under the plasma concentration-time curve from time zero to the last measured time, 24 h, in plasma (AUC(0-24 h)) was significantly different among the three doses (the AUC(0-24 h) based on 20 mg/kg/day was 2.33, 7.00 and 4.19 microg h/ml for 20, 80 and 320 mg/kg/day, respectively). Similar results were also obtained from DA-8164, a metabolite of DA-8159; the AUC(0-24 h) of DA-8164 after dose-normalized to 20 mg/kg/day of DA-8159 were 2.74, 5.00 and 1.68 microg h/ml, respectively.

Pharmacokinetics of DA-8159, a new erectogenic, after intravenous and oral administration to rats: hepatic and intestinal first-pass effects.

The purposes of this study were to report dose-independent (after intravenous administration) and dose-dependent (after oral administration) area under the curve of plasma concentration versus time from time zero to time infinity (AUC), and gastric, intestinal, and/or hepatic first-pass effects (after intravenous, intraportal, intragastric, and intraduodenal administration) of DA-8159 [5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidine-7-one], a new erectogenic, in rats. After intravenous administration at doses of 5, 10, and 30 mg/kg, the AUCs and time-averaged total body clearances (CLs) were dose-independent. However, the AUCs were dose-dependent after oral administration at doses of 20, 30, 50, and 100 mg/kg. This result could be due to saturation of first-pass effects at high doses. The extent of absolute oral bioavailability (F) of DA-8159 was 38.0% at a dose of 30 mg/kg. Considering almost complete absorption of DA-8159 from rat gastrointestinal tract ( approximately 99% of oral dose of 30 mg/kg), the low F could be due to considerable hepatic, gastric, and/or intestinal first-pass effects. After intravenous administration at three doses, the CLs were considerably slower than the reported cardiac output in rats, suggesting almost negligible first-pass effect of DA-8159 in the heart and lung. The AUCs were not significantly different between intragastric and intraduodenal administration of DA-8159 at a dose of 30 mg/kg (131 and 127 microg x min/mL), suggesting that gastric first-pass effect of DA-8159 was almost negligible in rats. However, the values were significantly smaller than that after intraportal administration (311 microg x min/mL), indicating considerable intestinal first-pass effect of DA-8159 in rats of approximately 58% of the oral dose. Approximately 23% of DA-8159 at a dose of 30 mg/kg absorbed into the portal vein was eliminated by the liver (hepatic first-pass effect) based on AUC difference between intravenous and intraportal administration (the value, 23%, was equivalent to approximately 9.6% of oral dose). The low F of DA-8159 after oral administration at a dose of 30 mg/kg to rats was mainly due to considerable intestinal ( approximately 58%) first-pass effects.