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.     

Gender differences in the hepatic elimination and pharmacokinetics of lobeglitazone in rats

The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration at a dose of 1 mg/kg and oral administration at doses of 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration–time curve from time zero to infinity (AUC_inf) after intravenous administration was approximately 7.1 times higher in female rats than in male rats. In addition, the AUC_inf in the case of oral administration was at least 4.4 times higher in female rats and appeared to increase in proportion to the dose in both genders. The in vitro half‐lives were 18.8 ± 4.45 min and 60.7 ± 11.2 min, as evidenced by incubating liver microsomes obtained from male and female rats, respectively. As a result, the estimated CL_int for LB for male rat liver microsomes (0.0779 ± 0.0233 ml/min/mg protein) was much higher than that for female rat liver microsomes (0.0233 ± 0.0039 ml/min/mg protein, p < 0.05). These observations suggest that there are gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. Copyright © 2015 John Wiley & Sons, Ltd.     

The pharmacokinetics of bendazac-lysine and 5-hydroxybendazac,its main metabolite,in patients with hepatic cirrhosis

Summary We have studied the pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, in 11 patients with hepatic cirrhosis after the oral administration of a single 500 mg tablet of bendazac-lysine, and compared them with those obtained from 10 healthy adults.The rate of absorption of bendazac, as assessed by t_max and C_max, is similar in patients and in healthy subjects.The drug is eliminated mostly by metabolism in healthy adults, more than 60% of the dose being excreted in the urine as 5-hydroxybendazac and its glucuronide. Hepatic insufficiency impairs this metabolism, a two-fold decrease in apparent plasma clearance (CL/f) being observed in the patients.Although the plasma unbound fraction of bendazac is increased in patients (the drug is highly bound to plasma albumin), the apparent volume of distribution (V/f) is unchanged. In consequence, the half-life of bendazac is increased two-fold in the patients.Impairment of metabolism decreases the formation of 5-hydroxybendazac, but metabolism remains the main route of its elimination. Renal excretion of bendazac accounts for about 10% of the dose in both patients with cirrhosis and healthy subjects.We conclude that in patients with severe hepatic insufficiency the daily dose of bendazac-lysine should be havled.     

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.     

Faster clearance of mirodenafil in rats with acute renal failure induced by uranyl nitrate: contribution of increased protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2

Objectives It has been reported that mirodenafil is primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2, 2B1/2, 2D1 and 3A1/2 in rats. It has also been reported that the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 increases and that of hepatic CYP2D1 decreases in rats with acute renal failure induced by uranyl nitrate (U‐ARF rats). Thus, the pharmacokinetics of mirodenafil were studied in control and U‐ARF rats. Methods The pharmacokinetic parameters of mirodenafil and SK3541 (a metabolite of mirodenafil) were compared after the intravenous and oral administration of mirodenafil at a dose of 20 mg/kg to U‐ARF and control rats. Key findings After interavenous administration of mirodenafil to U‐ARF rats, the total area under the concentration–time curve (AUC) of mirodenafil was significantly smaller (36.5% decrease) than controls, possibly due to the significantly faster non‐renal clearance (66.1% increase; because of increase in the protein expression of hepatic CYP3A1) than controls. After the oral administration of mirodenafil to U‐ARF rats, the AUC of mirodenafil was also significantly smaller (47.8% decrease) due to the increase in the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 compared with controls. Conclusions After both intravenous and oral administration of mirodenafil to U‐ARF rats, the AUC_SK3541/AUC_mirodenafil ratios were comparable with that in controls and this could be due to further metabolism of SK3541 in rats.     

Pharmacokinetics of a new reversible proton pump inhibitor,YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5–20 mg kg⁻¹, to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50–200 mg kg⁻¹, to rats, the area under the plasma concentration–time curve from time zero to 12 or 24 h (AUC_{0–12 h} or AUC_{0–24 h}) was proportional to the oral dose of the drug, 50–100 mg kg⁻¹, however, the AUC_{0–24 h} value at 200 mg kg⁻¹ increased with less proportion to the dose increase (324, 689, and 815 μg · min mL⁻¹ for 50, 100, and 200 mg kg⁻¹, respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg⁻¹, respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg⁻¹. The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg⁻¹, was approximately 70% (116 versus 163 μg · min mL⁻¹) of that after iv administration of the drug, 5 mg kg⁻¹, to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5–20 mg kg⁻¹, to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg⁻¹, to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5–20 mg kg⁻¹, to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC_{0–10 h} values were not significantly different (96.8 versus 98.2 μg · min mL⁻¹) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs. Copyright © 1998 John Wiley & Sons, Ltd.     

Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats

To evaluate the metabolic interaction between host and gut microflora on drug metabolism, pseudo germ‐free rats were prepared with an antibiotics cocktail to change their gut conditions. The usefulness of the pseudo germ‐free model was evaluated for observing the DMPK of acetaminophen (APAP). Pseudo germ‐free rats were prepared by orally administering antibiotic cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered to control and pseudo germ‐free rats. The plasma concentration of APAP and its six metabolites were quantified using a validated LC‐MS/MS method. A non‐compartment model estimated the pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve (AUC; AUC_metabolite/AUC_APAP) were also observed to evaluate the change of APAP metabolism. The AUCs of APAP and APAP‐Glth (glutathione) were higher and the AUC_APAP‐Sul/AUC_APAP (metabolic efficiency of sulfate conjugation) was lower in pseudo germ‐free rats than those in the control rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction of the sulphate supply, causing an increase of the AUC of APAP and APAP‐Glth. The activities of gut microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic APAP metabolism. These results indicate that gut microflora may play an important role in the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and gut microflora should be considered upon drug administration and pseudo germ‐free rats prepared in the present study can be competent for investigating the metabolic interaction between host and gut microflora on drug metabolism. Copyright © 2012 John Wiley & Sons, Ltd.     

Metabolism,oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats

The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro‐intestinal first‐pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K_m and V_max), the propensity for UDPGA‐dependent conjugation compared with NADPH‐dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague‐Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro‐intestinal first‐pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. Pharmacokinetic parameters were obtained by non‐compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration–time profiles for 10 and 25 mg/kg were consistent with high clearance (～3 L/hr/kg) and large volumes of distribution (8–12 L/hr/kg). The disposition was characterized by a terminal half‐life value of 3–4 h. After oral administration the plasma concentration–time profiles demonstrated fairly rapid absorption (t_max～1–2 h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at ～2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first‐pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. Copyright © 2009 John Wiley & Sons, Ltd.     

Effects of biliary excretion on the disposition of felodipine and metabolites in the rat

1. After i.v. and intraduodenal administration of ³H-felodipine to rats, approx. 50% of the dose was excreted in bile in the first 6 h. Total urinary and biliary recoveries after both administration routes were similar.

2. Neither unchanged felodipine nor oxidized pyridine metabolite was detected in bile. Bile collection had no effect on the blood concentration-time profiles of either compound.

3. Bile collection decreased the area under the blood concentration-time curve (AUC) of total, unidentified felodipine metabolites by 30%, and their urinary recovery by 50%.

4. Of the total metabolites excreted in bile, 40% was calculated to be subject to enterohepatic recycling.

5. The dose-normalized AUC of both felodipine and pyridine metabolite were decreased after intraduodenal administration of drug, indicating pre-systemic elimination of drug, and possibly of the pyridine, in the gut. Route of administration had no effect on the AUC of total unidentified metabolites.     

Comparison of two compartmental models for describing ranitidine's plasmatic profiles.

The plasmatic profiles of 12 healthy volunteers after oral administration of ranitidine (150 mg) were studied considering two compartmental models. We observed the presence of two peaks. The proposed mechanism responsible for the existence of secondary peaks includes enterohepatic recirculation and the existence of multiple sites of absorption along the gastrointestinal tract. For characterizing the pharmacokinetic aspect of the drug, both phenomena were described using two compartmental models. We calculated the pharmacokinetic parameters and statistical tests after fitting the data of each volunteer under both models proposed. Statistically significant differences were not found in the statistical test values but existed in the area under the curve (AUC) comparing between models. To decide which of the two proposed models gave the best approximation of the physiological phenomenon undergone, we studied the pharmacokinetic of the drug in the rat, an animal without gallbladder.After oral administration of ranitidine, the plasmatic profile of the animals showed at least two peaks. Less than 0.2% of an oral dose was recovered in bile as ranitidine. Therefore, and considering the rat has no post-absorptive depot from where the drug can be released discontinuously, enterohepatic recycling does not seem to contribute significantly to the occurrence of secondary peaks in the concentration-time profiles of rats.Considering the results, we proposed that the best model able to explain the plasmatic profiles found in man and rats after oral administration of ranitidine is the one that presents multiple sites of absorption along the gastrointestinal tract. It is important to define the correct model in the calculation of the AUC and so in the value of the absolute bioavailability.     

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.     

Effect of acute and chronic cadmium treatment on hepatic drug metabolism in male rats

The effect of acute and chronic cadmium administration on hepatic drug metabolism was investigated in the male rat. 3 days after the acute administration of cadmium by either the intraperitoneal (0.84 mg Cd/kg) or the oral (> 80 mg Cd/kg) route, there was a significant potentiation in duration of hexobarbital hypnosis and inhibition of hepatic microsomal metabolism of hexobarbital and aniline. Administration of cadmium in the drinking water at levels of 100 or 200 ppm Cd for periods of 2–12 weeks or at levels of 5 or 20 ppm Cd for 50 weeks did not produce alterations in either drug response or hepatic drug metabolism. Significant levels of metallothionein, a cadmium binding protein, found in the liver of the rats receiving cadmium chronically may offer an explanation for the observed differences in drug metabolism between the acute and chronic administration of cadmium. In additional studies, pretreatment of the rats with subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) intraperitoneally produced a tolerance to the alterations in drug metabolism induced by the previous cadmium dose (0.84 mg Cd/kg, i.p.). However, chronic cadmium treatment (5 or 20 ppm Cd for 50 weeks) did not impart any such tolerance to subsequently administered Cd (0.84 mg/kg) by the intraperitoneal route. The hepatic levels of metallothionein induced by the chronic cadmium treatment were only 30–60% of those induced by the subthreshold cadmium and thus may not have bound enough of the large challenge cadmium dose to produce the tolerance phenomenon.     

Pharmacokinetic evidence for the occurrence of extrahepatic conjugative metabolism of p-nitrophenol in rats

p-Nitrophenol (PNP), as a model compound for the study of conjugative metabolism, was administered intravenously to rats. PNP and its conjugated metabolites, i.e. PNP-glucuronide (PNP-Glu) and PNP-sulfate (PNP-Sul), were determined in body fluids by reversed-phase high-performance liquid chromatography using ion-pair systems. Linear pharmacokinetics was applicable in the dose range of 1.6 to 8 mg/kg. The metabolic clearance which was obtained from the area under the PNP blood concentration curve (AUC_iv) and from the excretion ratio of the total conjugates as PNP-Glu and PNP-Sul was so close to the hepatic blood flow that the PNP conjugation reactions seemed to be limited by the hepatic blood flow; that is, the hepatic extraction ratio (E_H) was expected to be 1. However, AUC_pv, following portal vein administration of PNP (4 mg/kg), was not zero but was significantly different from AUC_IV after the same dosing (P < 0.05). Consequently, comparison between the AUC values from both dosing routes and the excretion ratio of PNP-Glu and PNP-Sul gave an E_H of 0.43. Such a difference in E_H obtained by the two methods suggested a contribution by extrahepatic conjugative metabolism. It was shown that the intrinsic hepatic clearance obtained, assuming exclusively hepatic conjugative metabolism, was certainly overestimated. Furthermore, the results of the conjugation reaction in tissue homogenates suggested a contribution by extrahepatic glucuronidation.     

Pharmacokinetics of mirodenafil and its two metabolites,SK3541 and SK3544, after intravenous and oral administration of mirodenafil to streptozotocin-induced diabetes mellitus rats

1. The area under the curve (AUC) of mirodenafil after intravenous administration in diabetes mellitus induced by streptozotocin (DMIS) rats was significantly smaller (by 28.0?%) than the control value, and the AUC_SK3541/AUC_mirodenafil ratio was significantly greater (by 130?%) in DMIS rats. This may be explained by the significantly faster hepatic CL_int of mirodenafil, owing to increased hepatic CYP1A, CYP2B1/2, CYP2D, and CYP3A expression, and a faster hepatic blood flow rate, compared with control values.

2. The AUC of mirodenafil after oral administration was comparable between DMIS and control rats, possibly because of the comparable intestinal CL_int, which may be attributable to increased CYP1A2 expression and decreased CYP2D expression in the intestines of DMIS rats.

     

Improved Pharmacokinetic Characteristics of Ursolic Acid in Rats Following Intratracheal Instillation and Nose-Only Inhalation Exposure

Ursolic acid (UA) is a common pentacyclic triterpene phytochemical with various pharmacological activities. However, UA is classified as a class IV drug in BCS system and its development as an oral drug is limited. Pulmonary delivery is an effective way to improve the bioavailability of drugs with low absorption. In this study, the differences in pharmacokinetic behaviors of UA after pulmonary and oral administration was explored in rats. Compared with oral administration, the plasma concentration of UA increased rapidly after pulmonary administration, and the bioavailability increased about 80 times. UA instantly accumulated in the lungs after pulmonary administration, and the pulmonary AUC_0-t/dose increased by 114 times compared to oral dosing. Incubation experiments showed that the metabolism of UA in rat lung microsomes was significantly reduced compared with that in liver microsomes, in which the clearance rate of phase I and phase II metabolism was reduced by 14.7 times and 1.4 times respectively. These results indicated that pulmonary administration could improve the bioavailability of UA and reduce its metabolism. This study not only provides a preferable route of administration for the application of UA but also offers new insights for the development of phytochemical drug candidates with poor pharmacokinetic properties.     

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.     

Ipriflavone pharmacokinetics in mutant Nagase analbuminemic rats

Ipriflavone, a derivative of naturally occurring isoflavones, was primarily metabolized in rats via hepatic CYP1A1/2 and 2C11. Protein and mRNA expression of CYP1A2 in the liver, reported to be increased in mutant Nagase analbuminemic rats (NARs), should influence the pharmacokinetic parameters of ipriflavone. In this study, the contribution of hepatic CYP2C11 and intestinal CYP1A protein to the metabolism and the pharmacokinetic parameters of ipriflavone were examined after intravenous (20 mg/kg) and oral (200 mg/kg) administration to male Sprague–Dawley (control) rats and NARs. There was no change in the protein expression of hepatic CYP2C11. By contrast, CYP1A protein of the intestine increased by almost 100%. After the intravenous administration of ipriflavone to NARs, the Cl_nr and AUC were unchanged, suggesting that the contribution of the increase in protein expression and mRNA level of hepatic CYP1A2 to hepatic metabolism of the drug in NARs seemed to be almost negligible. However, after the oral administration of ipriflavone to NARs, the AUC was significantly lower than that in the control rats (53.0% decrease), possibly due to the increased intestinal CYP1A that resulted in increased intestinal metabolism and decreased gastrointestinal absorption of ipriflavone in NARs. Copyright © 2009 John Wiley & Sons, Ltd.     

Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor,leading to the irregular absorption profile in rats after oral administration

Purpose. This study was undertaken to elucidate the underlying mechanism of the irregular absorption profiles of COL-3, a matrix metalloproteinase inhibitor, with a double- or plateau-peak concentration after a single oral dose administration of COL-3 suspension to rats. Methods. The gastrointestinal absorption profiles of COL-3 in rats were assessed by comparing serum drug concentration curves after the following various modes of drug administration: oral and intraduodenal doses, oral doses of COL-3 in fine and coarse suspensions, intraduodenal dosing to the bile-duct intact and cannulated (BDC) rats, and oral doses with and without food. In addition, the biliary excretion of COL-3 in the BDC rats was examined. Results. Neither variable gastric emptying nor enterohepatic recycling was the source of the irregular gastrointestinal absorption of COL-3 in rats. Reduction in particle size, presence of food and endogenous bile emerged as the determinants of the oral absorption of COL-3 by enhancing the dissolution of the solid drug in the gastrointestinal fluids. Flip-flop of the absorption and elimination rate constants was noted only for COL-3 after intraduodenal administration of the coarse suspension to the BDC rats with the bile flow diverged out of the body. Conclusions. Variability in dissolution rate-limited absorption was the main cause of the irregular absorption of COL-3 after oral administration of its solid dosage form.     

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

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

Comparative evaluation of absorption,distribution, and excretion of YM758, a novel If channel inhibitor,between albino and non-albino rats

1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of ¹⁴C-YM758 monophosphate.

2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC_{0–1 h} between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism.

3. The distribution of the radioactivity derived from ¹⁴C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively.

4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.