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.     

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.     

Pharmacokinetics of amitriptyline and one of its metabolites, nortriptyline, in rats: little contribution of considerable hepatic first-pass effect to low bioavailability of amitriptyline due to great intestinal first-pass effect

Pharmacokinetics of amitriptyline and nortriptyline were evaluated after intravenous (2.5-10 mg/kg) and oral (10-100 mg/kg) administration of amitriptyline to rats. The hepatic, gastric, and intestinal first-pass effects of amitriptyline were also measured at a dose of 10 mg/kg. The areas under the plasma concentration-time curve (AUCs) of amitriptyline were dose-proportional following both intravenous and oral administration. After oral administration of amitriptyline, approximately 1.50% of the dose was not absorbed, the extent of absolute oral bioavalability (F) was approximately 6.30%, and the hepatic and intestinal first-pass effects of amitriptyline were approximately 9% and 87% of the oral dose, respectively. Although the hepatic first-pass effect was 78.9% after absorption into the portal vein, the value was only 9% of the oral dose due to considerable intestinal first-pass effect in rats. The low F of amitriptyline in rats was primarily attributable to considerable intestinal first-pass effect. This study proves the little contribution of considerable hepatic first-pass effect to low F of amitriptyline due to great intestinal first-pass effect in rats. The lower F value of amitriptyline in rats than that in humans (46 +/- 48%) was due to grater metabolism of amitriptyline in rats' liver and/or small intestine.     

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.     

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.     

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 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-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.     

Gastrointestinal first-pass effect of furosemide in rats

The first-pass effect of furosemide was investigated in rats. Furosemide intravenous solution (20 mg kg(-1) Lasix), was administered via the jugular vein and the portal vein, orally, and instilled directly into the duodenum of rats. The first-pass effects of furosemide by lung, heart, and liver seemed to be negligible in rats. The absolute bioavailability of furosemide was 28.9 and 48.3% after oral and intraduodenal administration, respectively. Based on the gastrointestinal (GI) recovery study, 68.3 and 69.5% of furosemide were found to have disappeared mainly due to absorption and/or metabolism from rat GI tract after oral and intraduodenal administration, respectively. The results indicate that gastrointestinal and intestinal first-pass effects of furosemide were approximately 40% (68.3-28.9%) and 20% (69.5-48.3%) of the dose, respectively.     

Dose‐dependent pharmacokinetics and first‐pass effects of mirodenafil,a new erectogenic,in rats

The pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, after intravenous (5, 10, 20 and 50 mg/kg) and oral (10, 20 and 50 mg/kg) administration of mirodenafil, and the first‐pass effect of mirodenafil after intravenous, oral, intraportal, intragastric and intraduodenal (20 mg/kg) administration of mirodenafil were evaluated in rats. The pharmacokinetics of mirodenafil and SK3541 were dose‐dependent after both intravenous and oral administration of mirodenafil due to the saturable hepatic metabolism of mirodenafil. After oral administration of mirodenafil, approximately 2.59% of the oral dose was not absorbed, the F value was approximately 29.4%, and the hepatic and gastrointestinal first‐pass effects of mirodenafil were approximately 21.4% and 54.3% of the oral dose, respectively. The low F value of mirodenafil in rats was mainly due to considerable hepatic and gastrointestinal first‐pass effects in rats. The equilibrium plasma‐to‐blood cell partition ratios of mirodenafil were independent of the initial blood mirodenafil concentrations of 1–10 µg/ml; the mean values were 1.08–1.21. The plasma binding values of mirodenafil to rat plasma was 87.8%. Copyright © 2009 John Wiley & Sons, Ltd.     

Gastrointestinal first-pass effect of YJA-20379-8, a new reversible proton pump inhibitor, in rats.

Since low bioavailability of YJA-20379-8 (3-butyryl-4-[5-R-(+)-methylbenzylamino]-8ethoxy-1,7-naph thy ridine), a new reversible proton pump inhibitor, has been reported after oral administration of the drug to rats, the first-pass organ of the drug was investigated in rats. YJA-20379-8, 50 mg kg(-1), was infused over 1 min via the jugular vein (n=5) or the portal vein (n=5), or was instilled directly into the stomach (n=5) or the duodenum (n=5). After intravenous or intraportal infusion of the drug, the total body clearance of YJA-20379-8 (18.1 and 19.7 mL min(-1) kg(- 1) based on plasma data) was considerably lower than the reported cardiac output (296 mL min(-1) kg(-1) based on blood data) in rats. This data indicated that the first-pass effect of YJA-20379-8 by the lung and heart was negligible. The areas under the plasma concentration-time curve from time zero to time infinity (AUC) after intravenous or intraportal administration of YJA-20379-8 (2760 and 2540 microg min mL(-1)) were not significantly different, indicating that the hepatic first-pass effect of the drug was also negligible in rats. After intragastric or intraduodenal instillation of YJA-20379-8, the extent of absolute oral bioavailability was 18.2 and 33.8%, respectively. Based on gastrointestinal recovery studies, approximately 86.5 and 91.2% of YJA-20379-8 was absorbed from rat gastrointestinal tract after intragastric or intraduodenal instillation, respectively. The data indicated that gastrointestinal and intestinal first-pass effects of YJA-20379-8 were approximately 68% (86.5-18.2) and 57% (91.2-33.8), respectively. The AUC(0-24h) values of YJA-20379-8 were significantly different between intragastric and intraduodenal instillation, indicating that the gastric first-pass effect of the drug was approximately 10% in rats. Therefore, it could be concluded that the low F value of YJA-20379-8 after oral administration of the drug could be due to a considerable (approx. 60%) intestinal first-pass effect in rats.     

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.     

Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect

1. Pharmacokinetics of liquiritigenin, a candidate for inflammatory liver disease, and its two glucuronide conjugates, M1 and M2, were evaluated in rats. The hepatic and gastrointestinal first-pass effects of liquiritigenin were also evaluated in rats.

2. After oral administration of liquiritigenin at a dose of 20?mg kg^?1, 1.07% of the dose was not absorbed from the gastrointestinal tract up to 24?h, and the F-value was only 6.68%. In vitro metabolism of liquiritigenin in S9 fractions of rat tissues showed that the liver and intestine were major tissues responsible for glucuronidation of liquiritigenin. The hepatic and gastrointestinal first-pass effects of liquiritigenin were approximately 3.67% and 92.5% of the oral dose, respectively.

3. Although the hepatic first-pass effect of liquiritigenin after absorption into the portal vein was 57.1%, the value was only 3.67% of the oral dose due to extensive gastrointestinal first-pass effect in rats. Therefore, the low F-value of liquiritigenin in rats was primarily attributable to an extensive gastrointestinal first-pass effect although liquiritigenin was well absorbed. Compared with rats, the higher F-value of liquiritigenin could be expected in humans.

     

Dose-independent pharmacokinetics of ondansetron in rats: contribution of hepatic and intestinal first-pass effects to low bioavailability

The pharmacokinetic parameters of ondansetron were evaluated after its intravenous (at doses of 1, 4, 8 and 20 mg/kg) and oral (4, 8 and 20 mg/kg) administration to rats. The gastric, intestinal and hepatic first-pass effects of ondansetron were also evaluated after its intravenous, oral, intraportal, intragastric and intraduodenal administration at a dose of 8 mg/kg to rats. After intravenous and oral administration of ondansetron, the drug exhibits dose-independent pharmacokinetics in rats. After oral administration of ondansetron at a dose of 8 mg/kg, the unabsorbed fraction was 0.0158 of the dose, the extent of absolute oral bioavailability (F) value was 0.0407, and the hepatic and intestinal first-pass effects were 40.0% and 34.2% of the oral dose, respectively. The low F of ondansetron in rats was mainly due to considerable hepatic and intestinal first-pass effects. The lower F of ondansetron in rats (4.07%) than that in humans (62+/-15%) was mainly due to greater hepatic metabolism of the drug in rats. Ondansetron was stable in the rat gastric juices and various buffer solutions having pHs ranging from 1 to 13. The equilibrium plasma-to-blood cells partition ratio of ondansetron was 1.74-5.31. Protein binding of ondansetron to fresh rat plasma was 53.2%.     

Atypical dose-route-dependent food effects of eplerenone in the dog: presence of food effects following intravenous dosing and lack of food effects of following oral dosing

This study was conducted to investigate why a food effect was observed following an intravenous dose of eplerenone (EP) in the dog, but not following oral dosing. Three female dogs were implanted with a chronic portal vein access port and received radiolabeled EP doses orally (15 mg/kg in solution) and intravenously (7.5 mg/kg via cephalic and portal veins) under fasted and fed conditions. Mean AUC values for EP after infusion through the cephalic vein were 23.0 +/- 2.7 and 18.2 +/- 1.1 h.microg/mL under fasted and fed conditions, respectively. Corresponding values after infusion through the portal vein were 20.7 +/- 3.2 and 12.9 +/- 1.3 h.microg/mL, respectively. After oral administration, EP was absorbed 82.0 +/- 6.9 and 98.0 +/- 8.3% under fasted and fed conditions; corresponding mean AUC values were 32.0 +/- 2.0 and 30.8 +/- 3.6 h.microg/mL, respectively. The AUC value for SC-70303 acid (the open lactone form of EP) was lower under fed conditions after cephalic vein infusion, but was greater under fed conditions after portal vein infusion or oral solution administration. The hepatic first-pass effect of EP was 12.6 +/- 6.3% under fasted conditions and 27.1 +/- 6.0% under fed conditions. Pharmacokinetic analysis of EP concentrations after portal vein infusion and oral administration showed that under fed conditions the rate constants for bile excretion and for liver metabolism and urinary excretion were increased while the rate constant for elimination and/or metabolism in the gastrointestinal tract was reduced. In conclusion, the apparent lack of food effect after oral administration was observed because enhanced clearance was compensated by increased absorption.     

Dose-independent pharmacokinetics of a candidate for diabetic neuropathy,SR-4668, after intravenous and oral administration to rats: Intestinal first-pass effect

Dose-independent pharmacokinetic parameters of SR-4668 were observed after intravenous (i.v.) administrations at doses of 25, 50, and 75 mg/kg and oral administrations at doses of 50, 100, and 150 mg/kg to rats. The hepatic, gastric, and intestinal first-pass effects of SR-4668 were also measured after i.v., intraportal (i.p.), intraduodenal (i.d.), and intragastric (i.g.) administrations at a dose of 50 mg/kg to rats. Although a considerable amount of orally administered SR-4668 was absorbed, the F was low--only 33%. This indicates considerable first-pass (gastric, intestinal, and/or hepatic) effects of SR-4668 in rats. After i.v. administrations, the total body clearances of SR-4668 were considerably slower than the reported cardiac output in rats, suggesting that the first-pass effects of SR-4668 in the lung and heart could be negligible, if any, in rats. The AUCs of SR-4668 were comparable between i.v. and i.p. administrations, suggesting that the hepatic first-pass effect of SR-4668 was not considerable in rats. The AUCs were also comparable between i.d. and i.g. administrations, suggesting that gastric first-pass effect was almost negligible in rats. However, the AUC after an i.d. administration was significantly smaller (approximately 55% decrease) than that after an i.p. administration, suggesting that the intestinal first-pass effect was approximately 55% of oral dose. The rests of the orally administered dose could be mainly due to degradation of SR-4668 in gastric juices; 77.3-95.6% of the spiked amount of SR-4668 were recovered after 4-h incubation in five human gastric juices. The above data suggested that the low F of SR-4668 could be mainly due to considerable intestinal first-pass effect in 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).     

Liver and Gastrointestinal First-pass Effects of Azosemide in Rats

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg^?) and intraportal (5 and 10 mg kg^?) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg^?) of the drug was significantly lower than that after intravenous administration (5 mg kg^?) of the drug (1000 vs 1270 μg min mL^?) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC_{0–8 h}) after oral administration (5 mg kg^?) of the drug was considerably smaller than that after intraportal administration (5 mg kg^?) of the drug (271 vs 1580 μg min mL^?) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC_{0–8 h} after oral administration (5 mg kg^?) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg^?) of the drug (271 vs 320 μg min mL^?), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

     

Pharmacokinetic Studies of 5-Fluorouracil after Oral and Intravenous Administration in Man

Abstract The pharmacokinetic conditions for oral administration of 5-fluorouracil (5-FU) were investigated in 16 patients with malignant liver tumours. The concentration of 5-FU in portal and systemic blood was determined by a microbiologic method every 10 min. during 2 hours after oral or intravenous administration of a standard dose of 250 mg 5-FU (～ 4 mg/kg b.wt.) or 15 mg 5-FU/kg b.wt. The drug was rapidly absorbed after oral administration with peak values within 10–30 min. 25% of the lower and 40% of the higher oral dose reached the systemic circulation. The reduction of systemic bio-availability was partly accomplished by a loss in the gastrointestinal tract and partly by extraction by the liver. The hepatic extraction ratio was calculated to 0.56 and 0.26 after the lower and the higher dose respectively indicating a saturable process. The availability of 5-FU was significantly higher in portal blood than in systemic blood after oral administration. The opposite conditions were found after intravenous administration. Thus, oral administration of 5-FU to patients with malignant liver tumours seems rational.