Dose-dependent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage, KR-31378, in rats

The dose-dependent pharmacokinetic parameters of a new neuroprotective agent for ischemia-reperfusion damage, KR-31378, were evaluated after intravenous and oral administration, 10, 20, and 50 mg/kg, to rats. After intravenous administration of 50 mg/kg, the dose-normalized (10 mg/kg) AUC (994 microg min/mL) was significantly greater than that at 10 (569 microg min/ml) and 20 (660 microg min/mL) mg/kg. This could be due to slower clearance (Cl) with increasing dosage (18.5, 14.6, and 10.2 mL/min/kg for 10, 20, and 50 mg/kg, respectively). The slower Cl with increasing dosage could be due to saturable metabolism of KR-31378 in rats and this could be supported by significantly slower Cl(nr) and significantly greater 24-h urinary excretion of the drug at 50 mg/kg than those at 10 and 20 mg/kg. After oral administration of 50 mg/kg, the dose-normalized (10 mg/kg) AUC (1160 microg min/mL) was significantly greater than that at 10 (572 microg min/mL) and 20 (786 microg min/mL) mg/kg. Note that the AUCs were comparable (not significantly different) between intravenous and oral administration at each dosage, indicating that the absorption from gastrointestinal tract was almost complete and the first-pass (gastric, intestinal, and hepatic) effect was not considerable after oral administration to rats.     

Pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats

This study reports the absorption, dose-linearity and pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats after i.v. and oral administration at doses of 5, 10 and 25 mg/kg on both occasions. Concentrations of KR-31831 were determined by a validated LC/MS/MS assay method. After i.v. injection, plasma concentration-time profiles showed multi-compartmental characteristics, and there were no significant differences in Cl (20.8-27.7 ml/min/kg) and dose-normalized AUC (178.1-231 microg x min/ml based on the 5 mg/kg dose) as a function of dose. However, Vss was significantly increased at the 25 mg/kg dose (4931 ml/kg) compared with those (2288-2421 ml/kg) at lower doses. Subsequently, t1/2 was increased from 143-159 min at the lower doses to 304 min at the 25 mg/kg dose. The altered VSS was found to be a result of reduced plasma protein binding at relatively high concentrations. Following oral administration (doses 5-25 mg/kg), the absolute oral bioavailability ranged from 37.8% to 46.3%, and there were no significant alterations in dose-normalized AUC, Tmax, Cmax and t1/2 as a function of dose. The extent of urinary excretion was low for both i.v. (0.35%-0.54%) and oral (0.13%-0.33%) doses. Further discussions on the chemical and microsomal stability were included. In conclusion, dose-independent absorption kinetics were observed at oral doses from 5 to 25 mg/kg in rats. Orally administered KR-31831 could be eliminated mainly by the liver metabolic pathway.     

Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats.

The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.     

Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effect.

The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration-time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 microg min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC(0-12 h) at 50 mg/kg (25.1, 18.3 and 49.2 microg min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 microg min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats.     

Dose-independent pharmacokinetics of a new reversible proton pump inhibitor,KR-60436, after intravenous and oral administration to rats: gastrointestinal first-pass effect

Dose-independent pharmacokinetic parameters of KR-60436, a new proton pump inhibitor, were evaluated after intravenous (i.v.; 5, 10, and 20 mg/kg) and oral (20, 50, and 100 mg/kg) administration to rats. The hepatic, gastric, and intestinal first-pass effects were also measured after iv, intraportal (i.p.), intragastric (i.g.), and intraduodenal (id) administrations to rats of a dose of 20 mg/kg. The areas under the plasma concentration-time curve from time to zero to time infinity (AUCs) were independent of iv and oral dose ranges studied; the dose-normalized AUCs were 83.0-104 microg. min/mL (based on 5 mg/kg) and 78.4-96.8 microg. min/mL (based on 20 mg/kg) for iv and oral administration, respectively. After an oral administration at a dose of 20 mg/kg, approximately 3% of the oral dose was not absorbed, and the extent of absolute oral bioavaliability (F) was estimated to be 18.8%. The AUCs of KR-60436 after i.g. and i.d. administration at a dose of 20 mg/kg were significantly smaller (82.4 and 57.5% decrease, respectively) than that after an i.p. administration at a dose of 20 mg/kg, suggesting that gastrointestinal first-pass effect of KR-60436 was approximately 80% of oral dose in rats (the gastric first-pass effect was approximately 25%). After an i.p. administration at a dose of 20 mg/kg, the AUC was 77.6% of an iv administration, suggesting that hepatic first-pass effect was approximately 22% of KR-60436 absorbed into the portal vein. Note that the value of 22% was equivalent to approximately 4% of the oral dose. Because only 17% of oral dose was absorbed into the portal vein, the low F of KR-60436 in rats was mainly due to considerable gastrointestinal first-pass effect, which was approximately 80% (the gastric first-pass effect was approximately 25%) of oral dose.     

Dose-dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR-33028 in rats

The dose-dependency of the pharmacokinetics of a new Na(+)/H(+) exchanger inhibitor, KR-33028 was evaluated in rats after intravenous and oral administration. After intravenous administration of KR-33028 (1, 5, 10 and 20mg/kg doses), the systemic clearance (Cl) was reduced and AUC was nonlinearly increased as a function of dose. The volume of distribution (V(ss)), however, remained unchanged as the dose was increased, which was consistent with unaltered plasma protein binding in vitro (unbound fraction = 0.09-0.12). Upon oral administration (2, 10 and 20mg/kg doses), KR-33028 was rapidly absorbed, and this was consistent with high Caco-2 P(app) values found in vitro. There were nonlinear increases in AUC and C(max), and the absolute oral bioavailability (F) was significantly increased as the dose was increased (F = 23.3%, 40.7% and 78.2% for 2, 10 and 20mg/kg doses, respectively). The extent of urinary excretion was low for both intravenous (0.5-0.7%) and oral (0.2-0.8%) doses. The reduced systemic clearance and increased oral bioavailability at high doses appears to be due to a saturable first-pass metabolism.     

Pharmacokinetics of a ginseng saponin metabolite compound K in rats

The absorption, dose-linearity and pharmacokinetics of compound K, a major intestinal bacterial metabolite of ginsenosides, were evaluated in vitro and in vivo. Using the Caco-2 cell monolayers, compound K showed moderate permeability with no directional effects, thus suggesting passive diffusion. After intravenous dose (i.v.; 1, 2, and 10 mg/kg), no significant dose-dependency was found in Cl (17.3-31.3 ml/min/kg), Vss (1677-2744 ml/kg), dose-normalized AUC (41.8-57.8 microg.min/ml based on 1 mg/kg) and t1/2. The extent of urinary excretion was minimal for both i.v. and oral doses. The extent of compound K recovered from the entire gastrointestinal tract at 24h were 24.4%-26.2% for i.v. doses and 54.3%-81.7% for oral doses. Following oral administration (doses 5-20 mg/kg), dose-normalized AUC (based on 5 mg/kg) was increased at the 20 mg/kg dose (85.3 microg.min/ml) compared with those at lower doses (4.50-10.5 microg.min/ml). Subsequently, the absolute oral bioavailability (F) was increased from 1.8%-4.3% at the lower doses to 35.0% at the 20 mg/kg dose. The increased F could be related to the saturation of carrier-mediated hepatic uptake and esterification of compound K with fatty acids in the liver.     

Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats

The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance.     

Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects

Pharmacokinetics of sildenafil after intravenous and oral administration at various doses and first-pass effect at 30 mg/kg were evaluated in rats. After intravenous administration (10, 30, and 50 mg/kg), the dose-normalized AUC values were proportional to intravenous doses studied. However, after oral administration (10, 30, and 100 mg/kg), the dose-normalized AUC values increased significantly with increasing doses, possibly due to saturation of metabolism of sildenafil in rat intestinal tract. After oral administration (30 mg/kg), approximately 0.626% was not absorbed and F was 14.6%. The AUC after intragastric administration was significantly smaller (71.4% decrease) than that after intraportal administration, however, the values were not significantly different between intragastric and intraduodenal administration. The above data suggested that intestinal first-pass effect of sildenafil was approximately 71% of oral dose in rats. The AUC values after intraportal administration were significantly smaller (49% decrease) than that after intravenous administration. This suggested that hepatic first-pass effect of sildenafil after absorption into the portal vein was approximately 49% of oral dose in rats (approximately 49% was equivalent to approximately 13.7% of oral dose). The low F of sildenafil at a dose of 30 mg/kg in rats could be mainly due to considerable intestinal first-pass effect.     

Pharmacokinetics of lithospermic acid B isolated from Salvia miltiorrhiza in rats

The absorption and pharmacokinetics of an active component of Salvia miltiorrhiza, lithospermic acid B (LSB), was investigated after intravenous and oral administration of doses of 10 or 50 mg LSB/kg to rats. Concentrations of LSB were determined by a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay method. After intravenous administration of 50 mg/kg, dose-normalized (10 mg/kg) area under the curve (AUC) (993 microg.min/ml) was significantly greater than that at 10 mg/kg (702 microg.min/ml). The slower clearance Cl-at 50 mg/kg could be due to saturable metabolism of LSB in rats, and this could be supported by significantly slower Cl(NR) and significantly greater 24-h urinary excretion of LSB at 50 mg/kg than at 10 mg/kg. Following oral administration of LSB, the extent of LSB recovered from the entire gastrointestinal tract at 24 h ranged from 41.2% to 23.3%. Although LSB was not detected (limit of quantitation 10 ng/ml) in plasma after oral dose of 10 mg/kg, the absolute oral bioavailability at 50 mg/kg was 5%. Since LSB was shown to have low permeability through the Caco-2 cell monolayers, the low bioavailability of LSB could be due to poor absorption and metabolism.     

Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability

The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.     

Dose-independent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage,KR-31543, after intravenous and oral administration to rats: hepatic and intestinal first-pass effects

The purpose of this study was to report dose-independent pharmacokinetics of KR-31543, a new neuroprotective agent for ischemia-reperfusion damage, after intravenous (iv) and oral (po) administration and first-pass effects after iv, intraportal, intragastric, and intraduodenal administration in rats. After iv (10, 20, and 50 mg/kg) and oral (10, 20, and 50 mg/kg) administration, the pharmacokinetic parameters of KR-31543 were dose independent. The extent of absolute oral bioavailability (F) was 27.4% at 20 mg/kg. Considering the amount of unabsorbed KR-31543 from the gastrointestinal tract at 24 h (4.11%), the low F value could be due to the hepatic, gastric, and/or intestinal first-pass effects. After iv administration of three doses, the total body clearances were considerably slower than the reported cardiac output in rats, suggesting almost negligible first-pass effect in the heart and lung in rats. The areas under the plasma concentration-time curves from time zero to time infinity (AUCs) were not significantly different between intragastric and intraduodenal administration of KR-31543 (20 mg/kg), suggesting that the gastric first-pass effect of KR-31543 was almost negligible in rats. However, the values were significantly smaller (305 and 318 microg x min/mL) than that after intraportal administration (494 microg x min/mL), indicating a considerable intestinal first-pass effect of KR-31543 in rats; that is, approximately 40% of the oral dose. Approximately 50% of KR-31543 absorbed into the portal vein was eliminated by the liver (hepatic first-pass effect) based on iv and intraportal administration (the value, 50%, was equivalent to approximately 30% of the oral dose). The low F value of KR-31543 after oral administration of 20 mg/kg to rats was mainly due to considerable intestinal (approximately 40%) and hepatic (approximately 30%) first-pass effects.     

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.     

Subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, after single and 4-week repeated oral administration in dogs.

The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 200 mg/kg/day (4.71 and 15.3 microg h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration.     

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.     

Hepatic and intestinal first-pass effects of oltipraz in rats

It was reported that the mean value of the extent of absolute oral bioavailability (F) of oltipraz at a dose of 20 mg/kg was 41.2% and only 2.68% of the oral dose was unabsorbed from the gastrointestinal tract in rats. Hence, the low F in rats could be due to considerable first-pass (gastric, intestinal and hepatic) effects. Hence, the first-pass effects of oltipraz were measured after intravenous, intraportal, intragastric and intraduodenal administration of the drug at a dose of 20 mg/kg to rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values between intragastric and intraduodenal administration (213 and 212 microg min/ml) in rats were almost similar, but the values were significantly smaller than that after intraportal administration (316 microg min/ml) in rats, indicating that gastric first-pass effect was almost negligible (due to negligible absorption of oltipraz from rat stomach), but the intestinal first-pass effect of oltipraz was considerable, approximately 32% of the oral dose. The hepatic first-pass effect of oltipraz was approximately 40% based on AUC values between intravenous and intraportal administration (319 versus 536 microg min/ml). Since approximately 65% of the oral oltipraz was absorbed into the portal vein, the value of 40% was equivalent to 25% of the oral dose. The low F of oltipraz in rats was mainly due to considerable hepatic and intestinal first-pass effects.     

Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data. Copyright (c) 2005 John Wiley & Sons, Ltd.     

Effects of water deprivation for 72 hours 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 in control rats and in rats with water deprivation for 72 h (rat model of dehydration). After intravenous administration in the rat model of dehydration, the Cl(nr) (0.654 versus 0.992 ml/min/kg) and Cl(r) (0.0273 versus 0.0784 ml/min/kg) values were significantly slower than in the controls. The slower Cl(nr) could be due mainly to a significantly smaller total amount of unchanged DA-7867 recovered from the gastrointestinal tract at 24 h (GI(24 h): 5.16% versus 9.21% of intravenous dose) due to impaired liver function in the rat model of dehydration. The slower Cl(r) could be due mainly to a significantly smaller 24 h urinary excretion of unchanged drug (Ae(0-24 h): 4.41% versus 7.75% of intravenous dose) due to urine flow rate-dependent Cl(r) of DA-7867 in the rat model of dehydration. Hence, the Cl was significantly slower in the rat model of dehydration (0.677 versus 1.07 ml/min/kg). After intravenous administration in the rat model of dehydration, the V(ss) of DA-7867 was significantly smaller than in the controls (396 versus 506 ml/kg) due mainly to significantly smaller free (unbound to plasma proteins) fractions of DA-7867 in plasma (6.90% versus 29.2%) in the rat model of dehydration. After oral administration in the rat model of dehydration, the AUC was significantly greater than that in controls (10800 versus 7060 microg min/ml) due mainly to a significantly smaller Ae(0-24 h) than in controls (3.50% and 6.17% of oral dose).     

Subacute toxicity and toxicokinetics of CJ-10882, a type IV phosphodiesterase inhibitor, after 4-week repeated oral administration in dogs.

The subacute toxicity and toxicokinetics of a type IV phosphodiesterase inhibitor, CJ-10882, were evaluated after single (on the 1st day) and 4-week (on the 27th day) oral administration of the drug, in doses of 0 (to serve as a control), 2, 10 and 50 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral doses of CJ-10882 resulted in salivation, vomiting, and atrophy of the thymus. The absolute toxic dose was 50 mg/kg/day and the level at which no adverse effects were observed was 2 mg/kg/day for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of CJ-10882 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of CJ-10882 were dose independent after a single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 8 h in plasma (AUC(0-8 h)) were not significantly different among three doses. The accumulation of CJ-10882 after 4-week oral administration was not notable at the toxic dose of 50 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-8 h) value at 50 mg/kg/day (0.132 microg h/ml) was not significantly greater than that at 10 mg/kg/day (0.131 microg h/ml). After 4-week oral administration, the dose-normalized C(max) and AUC(0-8 h) at 50 mg/kg/day were not significantly higher and greater, respectively, than those after the single oral administration.     

Effects of naringin on the pharmacokinetics of intravenous paclitaxel in rats

It was reported that paclitaxel is an inhibitor of hepatic P-glycoprotein (P-gp) and hepatic microsomal cytochrome P450 (CYP) 3A1/2, and that naringin is an inhibitor of biliary P-gp and CYP3A1/2 in rats. The purpose of this study was to report the effects of oral naringin on the pharmacokinetics of intravenous paclitaxel in rats. Oral naringin (3.3 and 10 mg/kg) was pretreated 30 min before intravenous (3 mg/kg) administration of paclitaxel. After intravenous administration of paclitaxel, the AUC was significantly greater (40.8% and 49.1% for naringin doses of 3.3 and 10 mg/kg, respectively), and Cl was significantly slower (29.0% and 33.0% decrease, respectively) than controls. The significantly greater AUC could be due mainly to an inhibition of metabolism of paclitaxel via CYP3A1/2 by oral naringin. The inhibition of hepatic P-gp by oral naringin could also contribute to the significantly greater AUC of intravenous paclitaxel by oral naringin.