scholarly journals Effects of Diabetes Mellitus Induced by Alloxan on the Pharmacokinetics of Metformin in Rats: Restoration of Pharmacokinetic Parameters to the Control State by Insulin Treatment

2008 ◽  
Vol 11 (1) ◽  
pp. 88 ◽  
Author(s):  
Myung G. Lee ◽  
Young H Choi ◽  
Inchul Lee
Keyword(s):  
Diabetes Mellitus ◽  
Oral Administration ◽  
Protein Expression ◽  
Intravenous Administration ◽  
Insulin Treatment ◽  
Pharmacokinetic Parameters ◽  
Mrna Levels ◽  
Altered Pharmacokinetic ◽  
Intravenous And Oral Administration ◽  
Control State

To test the effect of insulin treatment on the pharmacokinetics of metformin in rats with diabetes mellitus induced by alloxan (DMIA rats). The following results were reported from other studies. Metformin was metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats. In DMIA rats, the protein expression and mRNA levels of hepatic CYP2C11 and 3A1/2 decreased and increased, respectively. In rat model of diabetes mellitus induced by streptozotocin, the protein expression of hepatic CYP2D1 was not changed. The increase in hepatic CYP1A2, 2B1, and 2E1, and decrease in hepatic CYP2C11 in DMIA rats was returned to the controls by insulin treatment. METHODS. Metformin (100 mg/kg) was administered intravenously and orally to the control rats, DMIA rats, and DMIA rats with insulin treatment for 3 weeks (DMIA rats with insulin). RESULTS. After intravenous administration of metformin to the DMIA rats, the CLR and CLNR of the drug were significantly slower than the controls. After oral administration of metformin to the DMIA rats, the AUC of the drug was also significantly greater than the controls. After intravenous administration of metformin to the DMIA rats with insulin, the significantly slower CLNR of the drug in the DMIA rats was returned to the controls. The altered pharmacokinetic indices observed following intravenous and oral administration of metformin to DMIA rats returned to the control values in the DMIA rats with insulin. CONCLUSIONS. The significantly slower CLNR of metformin in the DMIA rats could be due to the decrease in hepatic CYP2C11 than the controls. The comparable CLNR of metformin between the DMIA rats with insulin and the control rats could be due to restoration of hepatic CYP enzyme changes in DMIA rats to the controls.

scholarly journals Changes in omeprazole pharmacokinetics in rats with diabetes induced by alloxan or streptozotocin: Faster clearance of omeprazole due to induction of hepatic CYP1A2 and 3A1

2007 ◽  
Vol 10 (4) ◽  
pp. 420 ◽  
Author(s):  
Dae Young Lee ◽  
Myung G. Lee ◽  
Hyun Sook Shin ◽  
Inchul Lee
Keyword(s):  
Diabetes Mellitus ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Mrna Levels ◽  
First Pass ◽  
Metabolic Activities ◽  
Intravenous And Oral Administration ◽  
Pharmacokinetics In Rats

Purpose. To investigate the effect of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS) on the pharmacokinetics of omeprazole in rats. It has been reported that omeprazole is primarily metabolized via hepatic CYP1A2, 2D1, and 3A1 in rats. The expression and mRNA levels of hepatic CYP1A2 and 3A1 increases in DMIA and DMIS rats, but the expression of hepatic CYP2D1 does not change in DMIS rats. In addition, the metabolic activities of intestinal CYP3A1/2 decreases in DMIS rats. Thus, it could be expected that the pharmacokinetics of omeprazole would be affected by changes in both DMIA and DMIS. Methods. Omeprazole was administered intravenously (20 mg/kg) and orally (40 mg/kg) to DMIA and DMIS rats and their respective controls. Results. After intravenous administration of omeprazole, the CLNR of the drug was significantly faster in DMIA (52.6 versus 67.4 mL/min/kg) and DMIS (50.2 versus 73.0 mL/min/kg) rats than the respective controls. However, after oral administration of omeprazole, the AUC was comparable between each type of diabetic rat and the respective controls. Conclusions. The significantly faster CLNR of intravenous omeprazole could be due to increased expression and mRNA levels of hepatic CYP1A2 and 3A1 in both types of diabetic rat. The comparable AUC of oral omeprazole could be due to a decrease in the intestinal first-pass effect of omeprazole caused by decreased intestinal CYP3A1/2 in diabetic rats. Following both intravenous and oral administration in DMIA and DMIS rats, the pharmacokinetics of omeprazole were similarly altered.

scholarly journals Effects of Escherichia coli Lipopolysaccharide on Telithromycin Pharmacokinetics in Rats: Inhibition of Metabolism via CYP3A

2007 ◽  
Vol 52 (3) ◽  
pp. 1046-1051 ◽  
Author(s):  
Joo H. Lee ◽  
Yu K. Cho ◽  
Young S. Jung ◽  
Young C. Kim ◽  
Myung G. Lee
Keyword(s):  
Escherichia Coli ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Microsomal Cytochrome P450 ◽  
Intravenous And Oral Administration ◽  
Inhibition Of Metabolism ◽  
Escherichia Coli Lipopolysaccharide

ABSTRACT It has been reported that telithromycin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP) 3A1/2 in rats and that the expression of hepatic and intestinal CYP3A decreases in rats pretreated with Escherichia coli lipopolysaccharide (ECLPS rats; an animal model of inflammation). Thus, it is possible that the area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) of intravenous and oral telithromycin is greater for ECLPS rats than for the controls. To assess this, the pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration (50 mg/kg). After intravenous administration of telithromycin, the AUC0-∞ was significantly greater (by 83.4%) in ECLPS rats due to a significantly lower nonrenal clearance (by 44.5%) than in the controls. This may have been due to a significantly decreased hepatic metabolism of telithromycin in ECLPS rats. After oral administration of telithromycin, the AUC0-∞ in ECLPS rats was also significantly greater (by 140%) than in the controls and the increase was considerably greater than the 83.4% increase after intravenous administration. This could have been due to a decrease in intestinal metabolism in addition to a decreased hepatic metabolism of telithromycin in ECLPS rats.

Pharmacokinetic Evaluation of 3′-Azido-2′, 3′-Dideoxyuridine-5′-O-Valinate-Hydrochloride as a Prodrug of the Anti-HIV Nucleoside 3′-Azido-2′, 3′-Dideoxyuridine

2003 ◽  
Vol 14 (5) ◽  
pp. 263-270
Author(s):  
Linghui Kong ◽  
John S Cooperwood ◽  
Shu-Hui Christine Huang ◽  
Chung K Chu ◽  
F Douglas Boudinot
Keyword(s):  
Oral Administration ◽  
Intravenous Administration ◽  
Oral Bioavailability ◽  
Half Life ◽  
Dose Range ◽  
Parent Compound ◽  
Terminal Phase ◽  
Pharmacokinetic Parameters ◽  
Intravenous And Oral Administration ◽  
Anti Hiv

3′-Azido-2′, 3′-dideoxyuridine (AZDU, AzddU, CS-87) has been shown to have potent anti-HIV activity in vitro. However, the compound exhibits a relatively short half-life and incomplete oral bioavailability in humans. In an effort to improve the pharmacokinetic properties of AZDU, prodrug 3′-azido-2′,3′-dideoxyuridine-5′- O-valinate hydrochloride (AZDU-VAL) was synthesized by the esterification of 5′-OH function in AZDU. The objective of this study was to investigate the biotransformation and pharmacokinetics of AZDU-VAL along with its antiviral parent compound AZDU following intravenous and oral administration to rats. Adult male Sprague-Dawley rats were administered AZDU or AZDU-VAL by intravenous injection or oral gavage. Concentrations of AZDU-VAL and AZDU were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. The bioavailability of AZDU after oral administration was approximately 53%. The terminal phase half-life of the nucleoside analogue ranged between 0.6 h after intravenous administration and 1 h following oral administration. In vivo the prodrug was rapidly and efficiently biotransformed to yield AZDU following intravenous and oral administration. The apparent availability of AZDU was virtually complete following oral administration of prodrug AZDU-VAL averaging 101%. The bioavailability of AZDU following intravenous administration of AZDU-VAL averaged 106%. In summary, the disposition of AZDU was dose dependent over the dose range of 25–100 mg/kg. Renal clearance and steady state volume of distribution were lower at the higher dose level. Prodrug AZDU-VAL demonstrated improved oral bioavailability as evidenced by complete absorption and efficient bioconversion to AZDU. The results suggest that AZDU-VAL may be a promising prodrug for the delivery of AZDU.

scholarly journals Pharmacokinetic Interaction Between Oltipraz and Silymarin in Rats

2009 ◽  
Vol 12 (1) ◽  
pp. 1 ◽  
Author(s):  
Min Kyung Kang ◽  
Soo Kyung Bae ◽  
Jin Wan Kim ◽  
Myung Gull Lee
Keyword(s):  
Oral Administration ◽  
Intravenous Administration ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Intravenous And Oral Administration ◽  
Single Intravenous Administration

ABSTRACT. Purpose: To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague–Dawley rats. Methods: Oltipraz (single doses of 10 and 30 mg/kg for intravenous and oral administration, respectively), silymarin (single doses of 50 and 100 mg/kg for intravenous and oral administration, respectively, and 14 days oral administration of 100 mg/kg), alone and together were administered to control rats. Results: The pharmacokinetic parameters of oltipraz did not significantly altered by silymarin. However, after intravenous administration of the drugs together, the AUCs of unconjugated, conjugated, and total (unconjugated plus conjugated) silibinin were significantly different (32.7% decrease, and 32.1% and 27.2% increase, respectively), and total and (CL) and non-renal (CLNR ) clearance of unconjugated silibinin were significantly faster (49.4% and 61.1% increase, respectively) than those of silymarin alone (without oltipraz). After oral administration of silymarin with or without oltipraz, however, the pharmacokinetic parameters of unconjugated, conjugated, and total silibinin were comparable. Conclusions: After single intravenous administration of the drugs together, the AUC of unconjugated silibinin was significantly smaller, but that of both conjugated and total silibinin was significantly greater. This could have been due to an increase in the formation of conjugates (glucuronidation and sulfation) of silibinin as induced by oltipraz. After simultaneous oral administration of the drugs, however, the AUCs (or AUC0−12 h) of unconjugated, conjugated, and total silibinin were comparable.

scholarly journals Pharmacokinetics of Luteolin and Metabolites in Rats

2008 ◽  
Vol 3 (12) ◽  
pp. 1934578X0800301 ◽  
Author(s):  
Sasiporn Sarawek ◽  
Hartmut Derendorf ◽  
Veronika Butterweck
Keyword(s):  
Oral Administration ◽  
Intravenous Administration ◽  
Plasma Concentrations ◽  
Maximum Level ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Oral Solution ◽  
Pharmacokinetic Parameters ◽  
Elimination Phase ◽  
Intravenous And Oral Administration

The pharmacokinetic parameters of luteolin and its glucuronide/sulfate conjugates were studied in rats after a single 50 mg/kg dose of luteolin administered as intravenous bolus or oral solution. Plasma and urine samples were enzymatically hydrolyzed to determine conjugate concentrations of luteolin. Noncompartmental analysis revealed a half-life of 8.94 h for free (unconjugated) and 4.98 h for conjugated luteolin following intravenous administration. Following oral administration, plasma concentrations of luteolin attained a maximum level of 5.5 μg/mL at 5 min and decreased to below LOQ (100 ng/mL) after 1 h. Ke could not be calculated because the elimination phase was below LOQ. The low bioavailability (F) of luteolin, 4.10% at a dose of 50 mg/kg, is presumably due to the significant first pass effect. For i.v. administration, the maximum concentration of luteolin was 23.4 μg/mL at 0 h. The plasma concentration versus time profile of luteolin was biphasic, subdivided into a distribution phase and a slow elimination phase for oral and intravenous administration. Luteolin was found to have a large volume of distribution and a high clearance. Double peaks were found after intravenous and oral administration, suggesting enterohepatic recirculation.

scholarly journals Brain Targeting of anti-HIV Nucleosides: in vitro and in vivo Evaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

1994 ◽  
Vol 5 (5) ◽  
pp. 304-311 ◽  
Author(s):  
K. J. Doshi ◽  
F. D. Boudinot ◽  
J. M. Gallo ◽  
R. F. Schinazi ◽  
C. K. Chu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Brain Targeting ◽  
The Central Nervous System ◽  
Intravenous And Oral Administration ◽  
The Brain

Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg−1 of the active nucleoside was 3%. Following oral administration of 250 mg kg−1 ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-CI-ddP were 19–25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.

scholarly journals Flucloxacillin bone and soft tissue concentrations assessed by microdialysis in pigs after intravenous and oral administration

2021 ◽  
Vol 10 (1) ◽  
pp. 60-67
Author(s):  
Mathias A. F. Bendtsen ◽  
Mats Bue ◽  
Pelle Hanberg ◽  
Josefine Slater ◽  
Maja B. Thomassen ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Oral Administration ◽  
Cortical Bone ◽  
Bone Tissue ◽  
Intravenous Administration ◽  
Antimicrobial Prophylaxis ◽  
Subcutaneous Tissue ◽  
Group Iv ◽  
Continuous Administration ◽  
Intravenous And Oral Administration

Aims Flucloxacillin is commonly administered intravenously for perioperative antimicrobial prophylaxis, while oral administration is typical for prophylaxis following smaller traumatic wounds. We assessed the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration ( fT > MIC) for methicillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. Methods A total of 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every six hours during a 24-hour period. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT > MIC was evaluated using a low MIC target (0.5 μg/ml) and a high MIC target (2.0 μg/ml). Results Intravenous administration resulted in longer fT > MIC (0.5 μg/ml) compared to oral administration, except for cortical bone. In Group IV, all pigs reached a concentration of 0.5 μg/ml in all compartments. The mean fT > MIC (0.5 μg/ml) was 149 minutes (95% confidence interval (CI) 119 to 179; range 68 to 323) in subcutaneous tissue and 61 minutes (95% CI 29 to 94; range 0 to 121) to 106 minutes (95% CI 76 to 136; range 71 to 154) in bone tissue. In Group PO, 0/8 pigs reached a concentration of 0.5 μg/ml in all compartments. For the high MIC target (2.0 μg/ml), fT > MIC was close to zero minutes in both groups across compartments. Conclusion Although intravenous administration of flucloxacillin 1 g provided higher fT > MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Cite this article: Bone Joint Res 2021;10(1):60–67.

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