scholarly journals Effect of Mild and Moderate Liver Disease on the Pharmacokinetics of Isavuconazole after Intravenous and Oral Administration of a Single Dose of the Prodrug BAL8557

2009 ◽  
Vol 53 (11) ◽  
pp. 4885-4890 ◽  
Author(s):  
A. Schmitt-Hoffmann ◽  
B. Roos ◽  
J. Spickermann ◽  
M. Heep ◽  
É. Peterfaí ◽  
...  
Keyword(s):  
Liver Disease ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
Water Soluble ◽  
Liver Impairment ◽  
Related Liver Disease ◽  
Intravenous And Oral Administration

ABSTRACT Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [P < 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease.

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.

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 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 Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions

2019 ◽  
Vol 20 (20) ◽  
pp. 5029 ◽  
Author(s):  
Shengmin Yan ◽  
Bilon Khambu ◽  
Honghai Hong ◽  
Gang Liu ◽  
Nazmul Huda ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Diseases ◽  
Hepatic Metabolism ◽  
Pathological Changes ◽  
Hepatic Cells ◽  
Nuclear Factors ◽  
Non Coding Rnas ◽  
Related Liver Disease

Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.

scholarly journals Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Amit V. Desai ◽  
Laura L. Kovanda ◽  
William W. Hope ◽  
David Andes ◽  
Johan W. Mouton ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Aspergillosis ◽  
Filamentous Fungi ◽  
Aspartate Aminotransferase ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

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 Antiviral Effect of Orally Administered (−)-β-d-2-Aminopurine Dioxolane in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection

2007 ◽  
Vol 51 (9) ◽  
pp. 3177-3184 ◽  
Author(s):  
Stephan Menne ◽  
Ghazia Asif ◽  
Jannan Narayanasamy ◽  
Scott D. Butler ◽  
Andrea L. George ◽  
...  
Keyword(s):  
Oral Administration ◽  
Hepatitis Virus ◽  
Aqueous Solubility ◽  
Hepatic Metabolism ◽  
Antiviral Effect ◽  
Water Soluble ◽  
Woodchuck Hepatitis Virus ◽  
Fold Reduction ◽  
Dose Dependent

ABSTRACT (−)-β-d-2-Aminopurine dioxolane (APD) is a nucleoside prodrug that is efficiently converted to 9-(β-d-1,3-dioxolan-4-yl)guanine (DXG). DXG has antiviral activity in vitro against hepatitis B virus (HBV) but limited aqueous solubility, making it difficult to administer orally to HBV-infected individuals. APD is more water soluble than DXG and represents a promising prodrug for the delivery of DXG. A placebo-controlled, dose-ranging efficacy and pharmacokinetic study was conducted with woodchucks that were chronically infected with woodchuck hepatitis virus (WHV). APD was efficiently converted to DXG after oral and intravenous administrations of APD, with serum concentrations of DXG being higher following oral administration than following intravenous administration, suggestive of a considerable first-pass intestinal and/or hepatic metabolism. APD administered orally at 1, 3, 10, and 30 mg/kg of body weight per day for 4 weeks produced a dose-dependent antiviral response. Doses of 3 and 10 mg/kg/day reduced serum WHV viremia by 0.4 and 0.7 log10 copies/ml, respectively. The 30-mg/kg/day dose resulted in a more pronounced, statistically significant decline in serum WHV viremia of 1.9 log10 copies/ml and was associated with a 1.5-fold reduction in hepatic WHV DNA. Individual woodchucks within the highest APD dose group that had declines in serum WHV surface antigen levels, WHV viremia, and hepatic WHV DNA also had reductions in hepatic WHV RNA. There was a prompt recrudescence of WHV viremia following drug withdrawal. Therefore, oral administration of APD for 4 weeks was safe in the woodchuck model of chronic HBV infection, and the effect on serum WHV viremia was dose dependent.

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.

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