Altered Drug–Serum Protein Binding in the Genetically Obese Zucker Rat

Benedek, I. H.; Blouin, Robert A.

doi:10.1002/jps.2600740807

Cited by 5 publications

(2 citation statements)

References 15 publications

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“…In addition to differences in hepatic metabolism, other factors could contribute to differences observed in the PK between ZDF and SD rats. Altered plasma protein binding has been reported for propranolol and diazepam that are bound to plasma a1-acid glycoprotein, and phenytoin that is bound to albumin (Benedek et al, 1985), but not for the two PPAR agonists in obese Zucker rats (Kim et al, 2004). In the present study, all four hepatically cleared drugs displayed very low free fraction (,0.01) that could not be readily quantified in SD rat plasma.…”

Section: Discussionmentioning

confidence: 99%

Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats

Zhou¹,

Rougée²,

Bedwell³

et al. 2016

Drug Metabolism and Disposition

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The Zucker diabetic fatty (ZDF) rat, an inbred strain of obese Zucker fatty rat, develops early onset of insulin resistance and displays hyperglycemia and hyperlipidemia. The phenotypic changes resemble human type 2 diabetes associated with obesity and therefore the strain is used as a pharmacological model for type 2 diabetes. The aim of the current study was to compare the pharmacokinetics and hepatic metabolism in male ZDF and Sprague-Dawley (SD) rats of five antidiabetic drugs that are known to be cleared via various mechanisms. Among the drugs examined, metformin, cleared through renal excretion, and rosiglitazone, metabolized by hepatic cytochrome P450 2C, did not exhibit differences in the plasma clearance in ZDF and SD rats. In contrast, glibenclamide, metabolized by hepatic CYP3A, canagliflozin, metabolized mainly by UDP-glucuronosyltransferases (UGT), and troglitazone, metabolized by sulfotransferase and UGT, exhibited significantly lower plasma clearance in ZDF than in SD rats after a single intravenous administration. To elucidate the mechanisms for the difference in the drug clearance, studies were performed to characterize the activity of hepatic drug-metabolizing enzymes using liver S9 fractions from the two strains. The results revealed that the activity for CYP3A and UGT was decreased in ZDF rats using the probe substrates, and decreased unbound intrinsic clearance in vitro for glibenclamide, canagliflozin, and troglitazone was consistent with lower plasma clearance in vivo. The difference in pharmacokinetics of these two strains may complicate pharmacokinetic/ pharmacodynamic correlations, given that ZDF is used as a pharmacological model, and SD rat as the pharmacokinetics and toxicology strain.

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Section: Discussionmentioning

confidence: 99%

Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats

Zhou¹,

Rougée²,

Bedwell³

et al. 2016

Drug Metabolism and Disposition

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“…To test this hypothesis, the effect of phenytoin on the embryonic heart rate was determined in both DMEM and in pure rat serum obtained from SD rats. Phenytoin has been reported to be 86.4% bound to rat serum from SD rats at 15 mg/ml ( 5 60 mM) (Benedek et al, 1985); hence, the amount of free phenytoin in DMEM should be 7.35 times greater than in rat serum. The results show that phenytoin causes a concentration-dependent decrease in rat embryo heart rate in both DMEM and rat serum with the IC 50 about two-fold higher in the rat serum.…”

Section: The Effect Of Protein Bindingmentioning

confidence: 99%

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

Abela

Ritchie

Ababneh

et al. 2010

Birth Defects Research Pt B

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This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

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