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.     

The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms

Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 (non-insulin-dependent) diabetes without causing overt hypoglycaemia. Its clinical efficacy requires the presence of insulin and involves several therapeutic effects. Of these effects, some are mediated via increased insulin action, and some are not directly insulin dependent. Metformin acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates (e.g. lactate) and opposing the effects of glucagon. In addition, metformin can reduce the overall rate of glycogenolysis and decrease the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake into skeletal muscle is enhanced by metformin. This has been attributed in part to increased movement of insulin-sensitive glucose transporters into the cell membrane. Metformin also appears to increase the functional properties of insulin- and glucose-sensitive transporters. The increased cellular uptake of glucose is associated with increased glycogen synthase activity and glycogen storage. Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid (Randle) cycle. Increased glucose turnover, particularly in the splanchnic bed, may also contribute to the blood glucose-lowering capability of metformin. Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. Some other effects of metformin may result from changes in membrane fluidity in hyperglycaemic states. Metformin therefore improves hepatic and peripheral sensitivity to insulin, with both direct and indirect effects on liver and muscle. It also exerts effects that are independent of insulin but cannot substitute for this hormone. These effects collectively reduce insulin resistance and glucotoxicity in type 2 diabetes.     

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.     

First-Pass Effect of cis-3,4-Dichloro-N-methyl-N-(2-(l-pyrrolidinyl)-cyclohexyl)-benzamide (U-54494) in Rats— A Model with Multiple Cannulas for Investigation of Gastrointestinal and Hepatic Metabolism

A multiple cannulated rat model was utilized to investigate the relative contribution of the gut and liver as sites of first-pass metabolism of orally administered U-54494 A, an anticonvulsant drug candidate. Each rat received a dose of U-54494 A by oral, intraportal, and intravenous routes on three separate occasions. Intraportal and intravenous doses were administered through chronic cannulas surgically implanted in the portal vein and superior vena cava, respectively. Blood samples were collected over a 6-hr period from the superior vena cava cannula. The mean (n = 3) bioavailability of orally dosed U-54494A was 4.5 ± 1.1%, while that dosed intraportally was 19.1 ± 3.0%. The relative contribution of the gut and liver as sites of first-pass extraction and/or metabolism of orally administered drug was 69.9 ± 14.0% and 24.5 ± 12.2%, respectively. Approximately 35 to 40% of the total plasma clearance was attributed to the liver. The plasma concentrations of the four known metabolites of U-54494A were apparently higher for the oral and intraportal routes compared to that after intravenous administration. This investigation confirms that the low oral bioavailability of U-54494A in the rat can be primarily attributed to both extensive intestinal and hepatic first-pass metabolism.     

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.     

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.     

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.     

雷贝拉唑肝、肠首过效应研究

目的研究雷贝拉唑在大白兔体内经十二指肠、门静脉与外周静脉等不同方式及不同剂量给药时的药代动力学,并探讨肠道、肝脏首过效应分别对其生物利用度的影响。方法在建立新西兰大白兔肠道血管通路模型基础上,从十二指肠(ID1.5、3、6mg·kg-1)、门静脉(PV1.5、3mg·kg-1)及耳缘静脉(V0·75、1.5、3mg·kg-1)不同途径、不同剂量给药,各时间点取血,高效液相色谱法检测雷贝拉唑血药浓度,评价其药代动力学,并计算生物利用度及肠道与肝脏提取率。结果随给药剂量增大,ID、PV、V给药时AUC0-t(mg·L-1·h)、AUC0-∞(mg·L-1·h)、Cmax(mg·L-1)均随剂量增大而升高(P<0.05),但Tmax(h)、T21(h)等参数无差异(P>0.05),CL(L·h-1·kg-1)则随给药剂量增加而降低(P<0.05)。经十二指肠给药1.5mg·kg-1时生物利用度为7.4%,3mg·kg-1时生物利用度为8.3%,肝脏提取率分别为84.8%、81.2%,肠道提取率分别为51.2%、56%。结论在大白兔各种给药方式时雷贝拉唑AUC0-t(mg·L-1·h)、AUC0-∞(mg·L-1·h)及Cmax(mg·L-1)均存在明显剂量依赖性;十二指肠给药时生物利用度较低,并且不呈剂量依赖性,原因主要为在肠道与肝脏经历较广泛的首过代谢。     

Biliary excretion of the vasopressin analogue DDAVP after intraduodenal, intrajugular and intraportal administration in the conscious pig

The biliary excretion of the vasopressin analogue 1-deamino-8-D-arginine vasopressin (dDAVP) was determined in the pig after three administration routes, intrajugular venous, intraportal venous and intraduodenal. In all cases the biliary excretion was less than 1% of the administered dose. The plasma/bile concentration ratio was less than 1:1. A significant first-pass effect was found when the liver was exposed to a high intraportal dose of dDAVP. Possible uptake and degradation/biotransformation was evaluated by incubating [3H]dDAVP with liver tissue slices showing that [3H]dDAVP was rapidly removed from the incubation medium. The following conclusions can be drawn from these experiments: 1) The intestinal mucosa constitutes the major barrier to intestinal absorption of dDAVP. 2) dDAVP is excreted in bile in small amounts. 3) Indirect evidence suggests that the dDAVP molecule is degraded/biotransformed in the liver at its C-terminus.     

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.     

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.     

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.     

Effect of metformin on glucose metabolism in the splanchnic bed.

1. Use of the antihyperglycaemic agent, metformin, is often associated with a small rise in circulating lactate. This study investigates the source of the lactate and examines the effect of metformin on glucose metabolism by the intestine and liver of rats. 2. Changes in plasma glucose and lactate were measured in the inferior vena cava (IVC), hepatic portal vein (HPV), hepatic vein (HV) and aorta (A) after intrajejunal administration of metformin (50 and 250 mg kg-1) without and with glucose (2 g kg-1). 3. Metformin 250 mg kg-1 reduced the hyperglycaemic response to a glucose challenge, associated with a greater reduction of glucose concentrations in the HPV (average decrease of 33% at 60 and 120 min) than at other sites. 4. Both doses of metformin increased lactate concentrations in the glucose-loaded state: the highest concentration (2.5 fold increase) was recorded in the HPV 60 min after administration of 250 mg kg-1 metformin, with a high lactate concentration persisting in the HV at 120 min. Metformin 250 mg kg-1 also increased lactate concentrations in the basal state, with highest concentrations (2 fold increase) in the HPV. 5. Two hours after intrajejunal administration of metformin, 50 mg kg-1, rings of tissue from the small intestine showed an average 22% decrease in glucose oxidation ([14C]-glucose conversion to 14CO2) and a 10% increase in lactate production. Since glucose metabolism in the gut is predominantly anaerobic, metformin caused an overall 9.5% increase of intestinal glucose utilization.(ABSTRACT TRUNCATED AT 250 WORDS)     

In-vivo Assessment of Extrahepatic Metabolism of Paeoniflorin in Rats: Relevance to Intestinal Floral Metabolism

The extraction ratios of paeoniflorin in gut wall (E_G), liver (E_H) and lung (E_L) were assessed by comparing AUCs after various routes of its administration to estimate the first-pass effects and the metabolism by intestinal flora. Pulmonary extraction ratio of paeoniflorin was assessed by comparing AUCs calculated from venous and arterial plasma concentrations after its intravenous administration (0.5 mg kg^?1). The mean pulmonary extraction ratio was estimated to be 006. The hepatic extraction ratio (E_H was assessed by comparing AUCs after intraportal and intravenous administrations (0.5 and 5 mg kg^?1). The plasma concentration profiles of paeoniflorin after intraportal administration were very close to those after intravenous administration, suggesting a negligible hepatic extraction ratio of paeoniflorin. The AUC value after intraperitoneal administration (0.5 mg kg^?1) was greater than that after intraportal or intravenous administration. This finding suggests that paeoniflorin is not metabolized in the gut wall. The transference of paeoniflorin from the serosal side to the mucosal side was evaluated by the in-vitro everted sac method. The low intestinal permeability (194% at 60 min) was demonstrated by the comparison with phenobarbital (63.1% at 60 min). We conclude that paeoniflorin is not metabolized by gut wall, liver and lung, its poor absorption from the intestine results in extremely low bioavailability and the unabsorbed fraction of paeoniflorin is degraded by the intestinal flora.     

Gastrointestinal and hepatic first-pass metabolism of aspirin in rats

The first-pass effect of aspirin was measured in male Wistar rats by comparing the plasma concentration after intravenous, oral or intraportal administration (10 mg kg-1) of the drug. Approximately 88 and 86% of the dose was excreted mostly as salicylic acid and its conjugated forms, glucuronide and sulphate, in urine within 48 h of i.v. or oral administration, respectively. This suggests that the gastrointestinal absorption of aspirin was essentially complete in rats. On the average, the area under the plasma concentration-time curve for unchanged aspirin following oral dosing (AUCo) was 0.35 of that obtained following i.v. administration (AUCi.v.) and 0.53 of that following intraportal administration (AUCp). Therefore, orally administered aspirin is subject to first-pass metabolism both in the gut and in the liver of rats. The gastrointestinal first-pass effect is estimated to be relatively more important than the hepatic effect.     

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.     

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.     

Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat

Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg · kg ^–1.From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72±2% (sd). The first-pass fraction eliminated after oral administration was 85±7% (sd), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.This work was supported in part by grants from The Swedish Academy of Pharmaceutical Sciences.Parts of this investigation were presented at the symposium Factors Affecting the Action of Narcotics, Milan, Italy, July 1976.     

Insulin requirement for the antihyperglycaemic effect of metformin.

1. Insulin-dependent diabetic BB/S rats with little or no endogenous insulin were used to determine whether insulin is required for the acute antihyperglycaemic effect of metformin (dimethylbiguanide). 2. Metformin (250 mg kg-1, intrajejunally) did not lower the hyperglycaemia in BB/S rats in the absence of exogenous insulin, but metformin increased by 69% (P < 0.05) the blood glucose-lowering effect of exogenous insulin. 3. Metformin (250 mg kg-1, intrajejunally) improved glucose disposal in rats with a normal insulin response to an intravenous glucose challenge. Plasma glucose disappearance was increased from 0.7 +/- 0.1 to 2.5 +/- 0.1% min-1 (P < 0.05). 3. When the insulin response to glucose was suppressed with somatostatin and diazoxide, metformin improved glucose disposal to a similar extent to that in rats with a normal insulin response. Plasma glucose disappearance was increased from 0.24 +/- 0.02 to 1.0 +/- 0.1% min-1 (P < 0.01). 5. The results indicate that insulin is required for the acute antihyperglycaemic effect of metformin, but the extent of this effect is not proportional to the prevailing insulin concentration.