Biomedical subjects

Yukako Yoshikawa

Publications and source records attributed to Yukako Yoshikawa.

At least 19 recordsLinked to original sources

PubMed2004

In situ intestinal absorption studies on low molecular weight heparin in rats using labrasol as absorption enhancer.

Oral absorption of low molecular weight heparin (LMWH) is limited by its molecular size and negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and decrease the hospital expenses. Studies were aimed at evaluating Labrasol for improving intestinal absorption of LMWH. Formulations containing LMWH and Labrasol were administered to duodenum, jejunum, and ileum of the fasted rats. The doses of LMWH and Labrasol were 200 IU/kg and 50 mg/kg, respectively. Reversibility of absorption enhancing effect of Labrasol was assessed by administering LMWH to jejunum after 0.5 and 1 h of administration of Labrasol. The effect of different doses of Labrasol on LMWH absorption was studied by administering Labrasol at 50, 100, and 200 mg/kg doses. Administration of LMWH formulation tojejunum resulted in the highest plasma anti-Xa activity (0.50+/-0.03 IU/ml) compared to duodenum (0.19+/-0.03 IU/ml), and ileum (0.29 +/-0.06 IU/ml) and the anti-Xa levels were maintained above the therapeutic level for about 160 min. The absorption of LMWH was negligible when LMWH was administered at 0.5 and 1 h post-Labrasol administration. Increasing the dose of Labrasol has decreased the absorption of LMWH from jejunum. Labrasol increased the intestinal absorption of LMWH, and jejunum was found to be the best site of absorption. Intestinal membrane permeability changes induced by Labrasol were transient and reversible. Maintaining high drug concentration gradient across intestinal wall is important to obtain increased intestinal LMWH absorption.

Animals↗

PubMed2004

Pharmacodynamic-pharmacokinetic profiles of metformin hydrochloride from a mucoadhesive formulation of a polysaccharide with antidiabetic property in streptozotocin-induced diabetic rat models.

The antidiabetic property of a formulation containing metformin hydrochloride and detarium gum has been evaluated in streptozotocin model of experimental rats. Both the gum and metformin hydrochloride possess antidiabetic properties to varying degrees. The pharmacokinetics of metformin from the mucoadhesive dosage forms indicated that for metformin alone, the area under the curve (AUC) values were 125.6 and 135.6 mgh/ml at 200 and 400 mg/kg BW, respectively. For the mucoadhesive products using the same dose levels, the AUCs were modified to 102.4 and 150.2 in detarium gum and 59.9 and 80.4 in NaCMC. The results indicate that detarium gum is a good excipient for the formulation of metformin mucoadhesive delivery systems when compared with NaCMC. The gum also showed promising antidiabetic effect and should be cautiously used as it may lead to depressed blood-glucose levels beyond the desired levels.

Adhesiveness↗

PubMed2004

Evaluation of factors to decrease plasma concentration of an HIV protease inhibitor, saquinavir in ethanol-treated rats.

Although alcohol consumption is a factor in which the bioavailability of saquinavir (SQV) are retarded, the cause for this phenomenon remains to be uncertain. In the presence study, we examined factors to decrease plasma concentration of SQV in ethanol-treated rats. The ethanol-treated rats were prepared by making them freely access to 15% ethanol solution for 14 d (Day 14 rats). The exsorption clearance of SQV from the blood circulation to the jejunal lumen in the Day 14 rats increased by 6-fold as compared to ethanol non-treated (NT) rats. In the presence of 25 microM ketoconazole (KCZ) or 10 microM cyclosporin A (CsA) in the jejunal lumen, the plasma concentration of SQV in the portal vein increased significantly, and this effect of 10 microM CsA was superior to that of 25 microM KCZ. The biliary excretion clearance of SQV in Day 14 rats also increased by 1.8-fold as compared to that in the NT rats. The metabolic clearance rate (V(max)/K(m)) of SQV in the intestinal microsomes from the Day 14 rats increased significantly, while in the liver microsomes the V(max)/K(m) did not change. The phase II metabolism processes in the Day 14 rats based on UDP-glucuronosyltransferases and gultathion-S-tnrasferase activities were activated, however, they were not likely to be one of factors to decrease the bioavailability of oral SQV, because CYP3A activity in the liver and intestine was not activated to such an extent and SQV itself was not conjugated. These observations suggest that a main possible factor to explain the reducing effect on the SQV oral bioavailability during ethanol consumption is an enhanced efflux of SQV at the intestine and liver, where it is suggested that functional enhancement or excessive expression of P-glycoprotein is caused by ethanol consumption.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Evaluation of factors to decrease bioavailability of cyclosporin A in rats with gentamicin-induced acute renal failure.

Focusing on the disposition of cyclosporin A (CsA) in the liver and intestine, effects of gentamicin-induced acute renal failure (ARF) on the decreased oral bioavailability of CsA were evaluated in rats. The area under the CsA concentration-time curve (AUC) in ARF rats after oral administration (5 mg/kg) significantly decreased by 43% as compared to the control, while the apparent oral clearance significantly increased by 76% of the control. The portal AUC of CsA in ARF rats with bile flow decreased by 67% as compared to the control rats. Without bile flow, the portal AUC of CsA in control rats decreased by 50% as compared to those with bile flow, whereas ARF rats without bile flow showed no notable change as compared to those with bile flow. The AUC of CsA mono-oxidative metabolite via CYP3A (M-OH) in ARF rats after oral or intravenous administration increased significantly by 84% or 241%, respectively, while there was no difference in the portal M-OH between control and ARF rats, suggesting that the elimination of M-OH was prolonged because of nephrotoxicity. Although the exsorption clearance of CsA from the blood circulation to the intestine after intravenous administration to ARF rats decreased significantly as compared to the control; and basolateral-to-apical transport of CsA through Caco-2 monolayers was significantly retarded in the presence of uremic toxins, there was no significant change in the total body clearance of CsA between ARF and control rats. Moreover, there were no effects of uremic toxins on the protein binding of CsA in plasma. These observations suggest that hepatic or intestinal CYP3A and P-glycoproteine (P-gp) are not likely to be concerned with lowering the oral bioavailability of CsA, and that bile function under the ARF condition induced by gentamicin is responsible for a marked decrease in the fraction absorbed of CsA in the small intestine.

Acute Kidney Injury↗

PubMed2004

[Suppression of glucose absorption by various health teas in rats].

The inhibitory effects on the intestinal digestion and absorption of sugar of health teas that claim beneficial dietary and diabetes-controlling effects were compared in rats using portal cannulae. The measured durations were the times during which the elevation of portal glucose levels resulting from continuous intragastric infusion of sucrose or maltose was suppressed by concentrated teas. The teas investigated included salacia oblonga, mulberry, guava, gymunema, taheebo, yacon, and banaba. The duration of the inhibitory effect on the sucrose load of salacia oblonga, mulberry, and guava were 110 min, 20 min, and 10 min, respectively. In contrast, gymunema, taheebo, yacon, and banaba had no significant effect on the continuous infusion of sucrose. These results suggest that there is considerable difference in the efficacy of commercial health teas in influencing glucose absorption.

Animals↗

PubMed2004

Evaluation of fast disintegrating lansoprazole tablet in human subjects.

Fast disintegrating lansoprazole tablet (LFDT) has been developed as a multiple unit formulation and evaluated using human subjects as compared to the conventional lansoprazole (LPZ) capsule containing enteric coated granules. Twelve healthy male volunteers, who were confirmed as extensive metabolizers (EMs) based on the plasma levels of LPZ sulphone metabolite, were enrolled into the study and genotype of CYP2C19 was confirmed. They kept 30 mg LFDT in their mouths for 2 min and the saliva was recovered without swallow. Eight subjects did not show LPZ in their serum after intake. Although LPZ was detected in 4 subjects' serum, their concentrations were less than 5 ng/mL. LPZ was thought to be not absorbed from the oral cavity. LFDT was orally administered to 12 healthy male EMs at two doses, 15 mg and 30 mg, and serum LPZ concentrations were measured. The mean C(max) and AUC(0-24) were 474.1+/-254.0 ng/mL and 1105.3+/-1101.4 ng.h/mL (15 mg) and 992.8+/-384.3 ng/mL and 2216.5+/-1270.1 ng.h/mL (30 mg). By comparing to that obtained after oral administration of the same doses of LPZ capsule, serum LPZ concentration vs. time curve was almost the same level, i.e., C(max) and AUC(0-24) did not have significant differences. From these results, LFDT has been shown to be equivalent to LPZ capsule and will show the same acid suppressing effects in the clinical situation.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2003

Evaluation of oral formulations of gentamicin containing labrasol in beagle dogs.

Gentamicin (GM) is a polarized water-soluble compound having very poor intestinal membrane permeability resulting in low oral bioavailability. Labrasol was found to improve the intestinal absorption of GM in rats. In the present study, GM formulations containing labrasol were evaluated in beagle dogs after filling into hydroxypropylmethyl cellulose (HPMC) capsules wrapped with Eudragit L100 (Eud L) and Eudragit S100 (Eud S) films. The results of the in vitro drug release studies could not differentiate between two kinds of enteric capsules and among the three kinds of GM formulations. Oral administration of GM solution at a dose of 50.0 mg per dog of GM and 0.60 ml per dog of labrasol has resulted in Cmax values of 2.38 +/- 0.50 microg/ml and 2.30 +/- 0.42 microg/ml with Eud L and Eud S capsules, respectively. The AUC values obtained were also higher at 4.35 +/- 1.31 microg h/ml and 5.34 +/- 0.95 microg h/ml with Eud L and Eud S capsules, respectively. Formulation of GM as a suspension in labrasol has resulted in the decrease of Cmax values by two to four times and AUC values by > 2.5 times compared to the solution formulation. The above results indicate that solution formulation was better over the suspension. An absorbent, synthetic sponge was used to absorb GM solution formulation and encapsulated with Eud L and Eud S capsules. The Cmax and AUC values obtained with sponge formulation were higher than those of suspension formulations but were lower than solution formulations. There was no significant difference in the extent of GM absorption between Eud L and Eud S capsules used for encapsulating GM formulations.

Administration, Oral↗

PubMed2003

Highly sensitive quantification of vancomycin in plasma samples using liquid chromatography-tandem mass spectrometry and oral bioavailability in rats.

We developed a highly sensitive liquid chromatography-tandem mass spectrometry assay (LC-MS-MS) for a glycopeptide antibacterial drug, vancomycin (VCM), in rat plasma. After precipitating 100 micro l of plasma with 300 micro l of 10% trifluoroacetic acid-methanol (2:1, v/v), the supernatant was diluted with 300 micro l of distilled water and was passed through a filter. LC-MS-MS equipped with electrospray ionization in the positive ion mode used a pair of ions at 725/144 m/z for VCM in the multiple reaction-monitoring mode with a sample injection volume of 20 micro l. The calibration curve had a linear range from 0.01 to 20 micro g/ml when linear least square regression was applied to the concentration versus peak area plot. The drug in the sample was detected within 5 min. Precision, accuracy and limit of quantitation indicated that this method was suitable for the quantitative determination of VCM in rat plasma. Using this method, we defined for the first time that the oral bioavailability of VCM in rats was 0.069%. This method can be applied to basic pharmacokinetic and pharmaceutical studies in rats.

Administration, Oral↗

PubMed2003

Possibility of a patch system as a new oral delivery system.

A new oral patch system has been designed to increase the residence time of model drugs within the gastrointestinal tract. The system consisted of three layers (1) water-insoluble backing layer (2) drug-carrying adhesive layer composed of a model drug, fluorescein (FL) or fluorescein isothiocyanate-dextran (FD), and gel-forming polymer and (3) pH-sensitive enteric polymer. These three layers system was prepared as 3.0 mm diameter patches. As references, tablet containing FL or FD was prepared. In vitro dissolution studies showed that the mean dissolution time (MDT) of model drugs from patch preparation was 0.739+/-0.021 h for FL and 0.407+/-0.021 h for FD, which were longer than from tablet, 0.327+/-0.008 h for FL and 0.270+/-0.019 h for FD. The two test preparations were orally administered to beagle dogs in a crossover manner at a FL dose of 30 mg/dog and the measured plasma FL concentrations were used for pharmacokinetic analysis. With FL patch preparation, area under the plasma drug concentration vs. time curve (AUC) was 2.12+/-0.24 microgh/ml and mean residence time (MRT) was 4.60+/-0.18 h, which were greater than those of tablet, AUC was 1.52+/-0.16 microgh/ml and MRT was 3.18+/-0.09 h, respectively. Oral patch preparation also increased both AUC and MRT of FD, a model macromolecular drug, which was formulated into both patches and tablets and administered to dogs (30 mg/dog). The AUC and MRT of FD from the patch preparation were 1.11+/-0.13 microgh/ml and 5.58+/-0.55 h and from tablets were 0.53+/-0.08 microg h/ml and 4.09+/-0.29 h, respectively. These results suggest that oral patch preparation has as a potential a new oral delivery system to obtain a long residence time of drug in the gastrointestinal tract.

Administration, Oral↗

PubMed2003

Enhanced intestinal absorption of vancomycin with Labrasol and D-alpha-tocopheryl PEG 1000 succinate in rats.

Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic used for the treatment of infections caused by methicillin-resistant staphylococci. It is water soluble, having a high molecular weight, and poorly absorbed from the gastrointestinal tract. Mixtures of VCM with Labrasol and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared to improve oral absorption of VCM. Administration of VCM solution to rat ileum at a dose of 20 mg/kg did not result in detectable plasma VCM concentration. Formulation containing 50% of Labrasol resulted in a Cmax value of 5.86+/-0.97 microg/ml and an AUC(0-6h) value of 16.06+/-1.78 microgh/ml. Addition of TPGS to VCM solution at 12.5% concentration also increased the plasma VCM concentration with a Cmax value of 4.98+/-0.45 microg/ml. But the AUC(0-6 h) (9.87+/-1.90 microgh/ml) was significantly lower than that obtained with Labrasol. The addition of 5.0 and 25.0% TPGS to solutions of VCM containing 50% of Labrasol did not result in any significant increase either in Cmax or AUC(0-6 h) of VCM. Whereas the addition of 12.5% of TPGS has resulted in an increase in Cmax and AUC(0-6 h) by 2.2 and 2.4 times, respectively, suggesting that this concentration of 50% Labrasol and 12.5% TPGS (1:0.25) was optimum for improving intestinal absorption of VCM. A dose dependent decrease in the Cmax and AUC(0-6 h) values was observed when the dose of absorption enhancers was decreased by 50% with formulation containing Labrasol and TPGS in 1:0.25 ratio. The results of the study indicate that formulations containing Labrasol and TPGS improve intestinal absorption of hydrophilic macromolecular drug, VCM.

Animals↗

PubMed2003

Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats.

Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78+/-0.10 to 0.38+/-0.03 microg h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30+/-0.06 to 0.57+/-0.05 microg h/ml and from 17.63+/-1.66 to 4.18+/-0.94 microg h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake.

Administration, Oral↗

PubMed2003

Effect of glycerol-induced acute renal failure on the pharmacokinetics of lidocaine after transdermal application in rats.

In this study, the effect of glycerol-induced acute renal failure (ARF) on the pharmacokinetics of lidocaine after transdermal application was investigated in rats. Microdialysis method was applied in vitro and in vivo to the abdominal skin of rats. After topical application of 1% lidocaine, the cumulative amount of lidocaine permeated through the excised rat abdominal skin showed parallel effect between normal and ARF rats with no significant difference in the in vitro permeability coefficient of lidocaine between them, while area under the plasma concentration versus time curve of lidocaine in ARF rats increased significantly. The protein binding rate of lidocaine in ARF plasma and the blood vessel permeability to muscle tissues, assessed by beta-D-glucopyranosyl fluorescein isothiocyanate-labeled (FITC) albumin, increased significantly. After intravenous infusion of 5 mg/h/kg lidocaine, both of the total body clearance and the volume of distribution of lidocaine in the ARF rats decreased significantly. These results suggested that renal dysfunction did not have any effect on the skin permeability of lidocaine, but might change the plasma protein binding of drug and blood vessel permeability which led to high plasma concentration of lidocaine.

Acute Kidney Injury↗

PubMed2003

Effect of indinavir on the intestinal exsorption of amprenavir, saquinavir and nelfinavir after intravenous administration in rats.

To elucidate drug interaction between human immunodeficiency virus (HIV) protease inhibitors (PIs), the effect of indinavir (IDV) on the intestinal exsorption of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV) was investigated in rats using an in situ single perfusion method. IDV in the intestinal perfusate inhibited the exsorption of rhodamine 123 (Rho123), a known P-glycoprotein (P-gp) substrate, from blood into intestinal lumen in a concentration-dependent manner, and the inhibitory potency of 10 micro M IDV in the perfusate was close to that of 10 micro M cyclosporin A (CsA) in the perfusate. Ten micro M of IDV in the intestinal perfusate also decreased significantly the exsorption clearance of Rho123 after intravenous administration. The IDV concentration in this system was not likely to cause hepatic interaction between HIV PIs, because the plasma IDV concentration was far below its inhibition constants for other HIV PIs in the liver microsomes. Thus, 10 micro M of IDV was chosen to investigate the effect of this inhibition on the exsorption of APV, SQV and NFV. IDV in the intestinal perfusate markedly increased the exsorbed amounts of SQV and NFV but not APV after intravenous administrations. Their exsorption clearances, however, showed only a slight increasing tendency or remained unchanged. These findings suggest that in addition to P-gp inhibition, other factors such as CYP3A inhibition might be important in the drug interaction of IDV with APV, SQV and NFV after intravenous administration in rat small intestine. The results obtained in this study will provide useful information to discuss the interactions among PIs when a double protease therapy is used for in HIV-infected patients.

Animals↗

PubMed2003

Bioadhesive delivery of metformin using prosopis gum with antidiabetic potential.

The antidiabetic properties of prosopis gum alone and as a bioadhesive base for the delivery of metformin are presented. The bioadhesive value of the gum was commensurate with those of Carbopol 974-P and sodium carboxymethyl cellulose (NaCMC). The release of the drug was higher from prosopis gum based bioadhesive formulations than from NaCMC and Carbopol 974-P products. This was shown by the shorter time required to reach t(50) (the time required for 50% of the drug to be released) or t(20) (time required for 20% of the drug to be released) for the release of metformin. The gum showed moderate antidiabetic properties when used alone. In combination with metformin in a bioadhesive form, the glucose lowering effect was found to be synergistic. The areas under the plasma drug concentration vs. time curves (AUCs) for the bioadhesive combinations were similar to those of the drugs alone in an aqueous system. This shows that the gum did not interfere with absorption of the incorporated drug. However, the areas under the effect vs. time curves (AUECs) were much higher when combined in a bioadhesive form than with the drug alone. The AUCs obtained with NaCMC based bioadhesive formulations were relatively smaller than those of metformin in an aqueous system and the combinations of metformin and prosopis gum.

Adhesives↗

PubMed2002

Sensitive and simultaneous determination of HIV protease inhibitors in rat biological samples by liquid chromatography-mass spectrometry.

A sensitive and simultaneous liquid chromatographic-mass spectrometric (LC/MS) method for the determination of current four HIV protease inhibitors (PIs), indinavir (IDV), saquinavir (SQV), nelfinavir (NFV) and amprenavir (APV) in rat plasma and liver dialysate by a microdialysis method was described. An isocratic LC/MS method in combination with atmospheric pressure chemical ionization was developed for the determination of these four PIs in biological samples in the same run. The analytes including an internal standard were extracted from 100 microL of plasma or 150 microL of liver dialysate samples by salting-out with 100 microL of ice-cold 2 M K(3)PO(4) followed by ether extraction. The separation of analytes was carried out on a reversed-phase semi-micro column using 50% of acetonitrile containing 1% acetic acid as mobile phase at a flow rate of 0.2mL/min(-1). The separation was completed within 5 min. Precision, recovery and limits of detection indicated that the method was suitable for the quantitative determination of these PIs in rat plasma or liver dialysate. This simple, sensitive and highly specific LC/MS method is suitable for pharmacokinetic studies and therapeutic drug monitoring in AIDS patients who receive double protease therapy.

Animals↗

PubMed2002

Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model.

A Physiologically-based pharmacokinetic (PB-PK) model was developed to describe the aspects of pharmacokinetic interactions between five HIV protease inhibitors (ritonavir, amprenavir, nelfinavir, saquinavir, indinavir) in rats. To increase usefulness of this BP-PK model, liver, intestinal tissue and other organ were assumed as compartments in this model. Each compartment was linked with the blood flow and the blood-to-plasma concentration ratios of those drugs, and the absorption process in the intestinal tract was presumed as a first-order kinetics. In addition, this PB-PK model incorporates two elimination processes due to hepatic and intestinal metabolism constructed by in vitro metabolic clearance rates and inhibition constants between HIV protease inhibitors. Excellent agreements were obtained between the predicted and observed concentrations of HIV protease inhibitors in rat plasma after a 20 mg/kg oral dose or co-administration of two kinds of HIV protease inhibitors (amprenavir/indinavir, nelfinavir/amprenavir, saquinavir/amprenavir, amprenavir/ritonavir, indinavir/ritonavir, nelfinavir/ritonavir, and saquinavir/ritonavir) with each 20 mg/kg oral dose. However, underestimates in the predicted plasma concentrations of saquinavir, indinavir and amprenavir were observed during the terminal phase after co-administration with ritonavir or amprenavir, suggesting that a term of other inhibitory process, such as a mechanism-based inhibition, might be incorporated into this PB-PK model. This BP-PK model enables us to know useful information about pharmacokinetic interaction when HIV infected patients would receive double protease therapy.

Administration, Oral↗

PubMed2002

Absorption enhancing effect of labrasol on the intestinal absorption of insulin in rats.

The oral absorption enhancing effect of Labrasol has been studied in rats using insulin as a model peptide/protein drug. Insulin solution was prepared by dissolving insulin in pH 7.4 buffer followed by the addition of Labrasol. The insulin concentration was 50.0 IU/ml. The test insulin/Labrasol solution was administered to the jejunum, ileum and ascending colon of rats at 10.0 IU/kg. After administration, blood samples were collected for 5 h and serum glucose levels and insulin levels were measured. In another group of rats, insulin solution was injected intravenously at 1.0 IU/kg, and both serum glucose and insulin levels were measured. The pharmacological availability of insulin from Labrasol solution was found to be 3.9, 8.9 and 9.1% following jejunal, ileal and colonic administrations, respectively, by comparing the serum glucose level vs. time profiles obtained after intestinal and i.v. administrations. By comparing the serum insulin levels vs. time profiles, the bioavailability of insulin was found to be 0.25 and 0.20% for intra-ileum and colonic administrations, respectively. The hypoglycemic effect of insulin after intra-ileum administration showed a dose-dependency in the insulin dose range from 10.0 to 1.0 IU/kg. These results suggest the absorption enhancing effect of Labrasol on the intestinal absorption of insulin in rats.

Animals↗

PubMed2002

Hepatic and intestinal contributions to pharmacokinetic interaction of indinavir with amprenavir, nelfinavir and saquinavir in rats.

To elucidate the aspects of pharmacokinetic interactions among HIV protease inhibitors (PIs), we investigated the effects of indinavir (IDV) on the hepatic and intestinal first-pass metabolism of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV), in rats. After oral co-administration with IDV, the area under the concentration versus time curves (AUC) of APV, SQV and NFV increased significantly by 1.6-, 9.5- and 2.3-fold, respectively, compared with mono-administration. After intravenous administration, the AUC of APV, SQV and NFV also increased in the presence of IDV by 1.4-, 1.2- and 1.5-fold, respectively. Mean concentrations of APV, SQV and NFV in the liver extracellular fluid, measured using a liver microdialysis method, were very low compared with their Michaelis constants regardless of co-administration of IDV, suggesting that APV, SQV and NFV metabolism follows linear kinetics in the liver. This finding also indicates that metabolism of PIs depended on the metabolic clearance rate in the liver microsomes. The oral bioavailability of SQV in the presence of IDV increased markedly by 8.5-fold, and that of APV and NFV also increased by 1.2- and 1.5-fold, respectively. On the basis of the well-stirred model, the hepatic availabilities of APV, SQV and NFV in the presence of IDV increased by 1.1-, 1.4- and 1.5-fold, and the intestinal availabilities increased by 1.1-, 6.2- and 1.1-fold, respectively. These results suggest that both hepatic and intestinal metabolism were essentially involved in the interactions between IDV and other HIV PIs, and the degree of those contributions varied with each combination of HIV PIs.

Animals↗