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.     

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.     

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 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 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 KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage in dogs

Dose-dependent pharmacokinetic parameters of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage, were evaluated after intravenous and oral administration of the drug at doses of 5, 10 and 25 mg/kg to male beagle dogs. After intravenous administration, the dose-normalized (based on 5 mg/kg) areas under the plasma concentration-time curve from time zero to time infinity (AUC values, 725, 1450 and 2300 micro g min/ml for 5, 10 and 25 mg/kg, respectively) were significantly different among the three dose ranges studied; the value increased more proportionally as the dose increased. This could be due to slower total body clearance (Cl) with increasing doses (6.90, 3.46 and 2.17 ml/min/kg). The slower Cl value with increasing doses may be due to saturable metabolism of KR-31378 in dogs. After oral administration, the dose-normalized (based on 5 mg/kg) AUC values (833, 1450 and 1920 micro g min/ml) at 5 mg/kg were significantly smaller than those at 10 and 25 mg/kg. Note that the AUC values were comparable (not significantly different) between intravenous and oral administration at all doses studied, indicating that the absorption of KR-31378 from the gastrointestinal tract was essentially complete and the first-pass (gastric, intestinal and/or hepatic first-pass) effects were almost negligible in dogs.     

Intestinal first-pass effect of bumetanide in rats

The intestinal first-pass effect of bumetanide was investigated after intravenous and intraportal infusion, and intragastric and intraduodenal instillation of the drug to rats. The AUC(0-->8 h) values of bumetanide after intragastric and intraduodenal instillation of the drug, 10 and 20 mg/kg, were significantly smaller than AUC values after intraportal administration, suggesting that the gastrointestinal first-pass effect of bumetanide was considerable in rats. However, the AUC(0-->8 h) values of bumetanide between intragastric and intraduodenal instillation were comparable, suggesting that the gastric first-pass effect of bumetanide was almost negligible in rats. The AUC(0-->8 h) values of bumetanide after intraduodenal instillation were significantly smaller than AUC values after intraportal infusion at 10 (89.8 vs 569 microg min per ml) and 20 (304 vs 1230 microg min per ml) mg/kg, indicating that the first-pass organ(s) of bumetanide was intestine. The F values were 15.8 and 24.7% after intraduodenal instillation of bumetanide, 10 and 20 mg/kg, respectively. Approximately 76.1 and 76.5% of intraduodenally instilled bumetanide disappeared (as a result of absorption and first-pass effect) after 10 and 20 mg/kg, respectively. Therefore, it could be concluded that approximately 60. 3 and 51.8% of the oral dose of bumetanide disappeared by intestinal first-pass effect at 10 and 20 mg/kg, respectively.     

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-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.     

Dose-independent pharmacokinetics of metformin in rats: Hepatic and gastrointestinal first-pass effects

Pharmacokinetic parameters of metformin were evaluated after intravenous and oral administration (50, 100, and 200 mg/kg) in rats. The hepatic, gastric, and intestinal first-pass effects were also measured after intravenous, intraportal, intragastric, and intraduodenal administration (100 mg/kg) in rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values were dose-proportional after both intravenous and oral dose ranges studied. After oral administration (100 mg/kg), approximately 4.39% of oral dose was not absorbed and extent of absolute oral bioavailability (F) value was approximately 29.9%. The gastrointestinal first-pass effect of metformin was approximately 53.8% of oral dose in rats (the gastric and intestinal first-pass effects were approximately 23.1 and 30.7%, respectively), and the hepatic first-pass effect was approximately 27.1% after absorption into the portal vein. Since approximately 41.8% of oral metformin was absorbed into the portal vein, the value of 27.1% is equivalent to 11.3% of oral dose. The first-pass effects of metformin in the lung and heart were almost negligible in rats. The low F value of metformin in rats was mainly due to considerable gastrointestinal first-pass effects. The stability of metformin, distribution of metformin between plasma and blood cells, and factors affecting protein binding of metformin to 4% human serum albumin were also discussed.     

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.     

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%.     

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.     

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 and hepatic extraction of recombinant human parathyroid hormone, hPTH (1-34), in rat, dog, and monkey

The pharmacokinetics (PK) and hepatic extraction (E(H)) of human PTH (1-34), hPTH (1-34), were characterized in rat, dog, and monkey, following intraportal (IPO) and intravenous (IV) bolus administration. hPTH (1-34) was administered to Sprague-Dawley rats (2, 10, 100 microg/kg), beagle dogs (3, 6 microg/kg), and rhesus monkeys (6, 30 microg/kg). Serum concentrations of immunoreactive hPTH (1-34) were used to derive PK parameters. IPO bioavailability (F(IPO)) was determined by comparing dose-normalized serum exposure (i.e., AUC(IPO)/AUC(IV)). E(H) was estimated as 1-F(IPO). In all species, greater than dose-proportional increases in exposure (i.e., C(max) and AUC) were observed for both routes. Dose-dependent disposition (i.e., time-average clearance (CL) and half-life (t(1/2)) were observed in all three species. In rats, E(H) values of 71% (2 microg/kg), 35% (10 microg/kg), and <1% (100 microg/kg) were obtained. In dogs, E(H) values of 90% (3 microg/kg) and 66% (6 microg/kg) were obtained. In monkeys, E(H) values of 25% (6 microg/kg) and <1% (30 microg/kg) were observed. In conclusion, hPTH (1-34) is subject to hepatic first pass extraction in rat, dog, and monkey with evidence of saturation in the rat. Saturable hepatic extraction in dog and monkey is inconclusive due to the limited dose range investigated.     

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 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 chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent,in rats

Abstract

1.?Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1–8?mg/kg) or CRD (1.1–4.5?mg/kg) and their equivalent dose of DA-9701 to rats.

2.?Dose-proportional AUC and dose-independent clearance (10.3–12.1?ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478–0.899%).

3.?CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5?mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.