Binding of fluvastatin to blood cells and plasma proteins.

The binding of fluvastatin, an inhibitor of hydroxymethylglutaryl coenzyme A reductase, to plasma proteins and red blood cells of rat, dog, and human in vitro was determined by ultrafiltration. Additionally, the stereospecificity of fluvastatin binding to proteins and the potential interaction between fluvastatin and the highly protein bound drugs warfarin, salicylic acid, and glyburide were investigated. Only a small fraction of fluvastatin in blood was taken up by the blood cells, amounting to 19-33% in the rat and < or = 15% in dog and humans. The plasma:blood fluvastatin ratio in these species at 37 degrees C was > or = 1.4. In human blood, this ratio was temperature independent. In the plasma concentration range 25-50,000 ng/mL, fluvastatin was > or = 98% bound to proteins. The binding was concentration dependent in the rat, but not in the dog and human. Both enantiomers of fluvastatin were > 99% bound in normal human plasma, the binding of each being unaffected by the presence of the other. A major fluvastatin-binding protein in human plasma was albumin, whereas binding to alpha 1-acid glycoprotein was relatively weak and concentration dependent. At therapeutic concentrations in normal human plasma, the protein binding of fluvastatin (0.1 microgram/mL) was unaffected by warfarin (1-10 micrograms/mL), salicylic acid (50-150 micrograms/mL), and glyburide (0.1-1 micrograms/mL). Similarly, fluvastatin had no influence on the binding of these compounds. In diluted human albumin solution (29 microM), bound fluvastatin was displaced by all three co-solutes tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraperitoneal and intraportal administration of droloxifene to the Sprague-Dawley rat: assessing the first-pass effect.

1. Employing droloxifene as a probe substrate, we have compared the use of intraperitoneal injection and intraportal infusion, where the rate and duration of intraportal drug administration were designed to approximate those observed after oral drug delivery, as methods of discriminating between high first-pass hepatic extraction and poor oral absorption. 2. Intraperitoneal injection of droloxifene (1 mg/kg) yielded an AUC0-omega approximately twice that observed following intraportal infusion or oral delivery of equal doses. 3. Our findings suggest that hepatic first-pass metabolism may have been saturated following intraperitoneal drug administration due to the rapid rate of absorption and the corresponding high drug concentrations achieved. 4. Application of a model in which intraportal drug infusion rates are designed to mimic the oral absorption rate appears warranted under such circumstances.

The effect of oral dose volume on the absorption of a highly and a poorly water-soluble drug in the rat.

The influence of dose volume on drug absorption following oral administration of a highly and a poorly water soluble drug was examined in male Sprague-Dawley rats. A constant mass of each 14C-labeled compound was given via gavage in dose volumes of 1, 5, 10, and 20 mL kg-1. Blood levels, as well as the quantitative excretion of radioactivity, were measured following each treatment. No significant changes in either the rate or extent of absorption of the water soluble drug were detected. In contrast, the absorption rate of the poorly water soluble drug increased with higher dose volumes, whereas no changes in the extent of absorption were observed. Drug solubility and gastric emptying appeared to be important factors affecting the rate of absorption of the poorly water soluble drug. Since changes in dose volume may affect the absorption characteristics of orally administered compounds, and the extent of such changes may be dependent upon the physicochemical properties of the drug, it is apparent that dose volume is an important experimental variable to be considered in studies comparing absorption data.

First-pass metabolism and biliary recirculation of droloxifene in the female Sprague-Dawley rat.

1. Utilizing a validated ultrasensitive hplc assay (lower limit of quantitation 25 pg/ml), we characterized the disposition profile of droloxifene in the female Sprague-Dawley rat following intravenous, oral and intraportal administration. 2. The site and extent of first-pass metabolism and the extent of enterohepatic recirculation were investigated. 3. Our findings suggest that the intestine is neither a metabolic nor an absorptive barrier to the bioavailability of droloxifene in the female Sprague-Dawley rat and that first-pass hepatic extraction is approximately 70-80% following an oral dose of 1 mg/kg. 4. Employment of a modified linked-rat model revealed that droloxifene is subject to enterohepatic recirculation (approximately 5%) in the rat.

Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine [correction of pyrazolidinone-piperidine] growth hormone secretagogue.

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.