Evaluation of the effects of risedronate on hepatic microsomal drug metabolizing enzyme activities following administration to rats for 14 days: lack of an induction response.

Risedronate ([1-hydroxy-2-(3-pyridinyl)-ethylidene[bis]phosphonic acid] monosodium salt) was evaluated for induction of hepatic microsomal drug metabolizing enzymes in male and female Sprague Dawley rats (N = 4/sex/dose group). Main study animals received water (vehicle control), risedronate (0.1, 0.8, 4, or 16 mg/kg/day) or phenobarbital (80 mg/kg/day, positive control) by daily oral gavage for 14 consecutive days. Recovery study animals received water, risedronate (16 mg/kg/day) or phenobarbital (80 mg/kg/day) by daily oral gavage for 14 consecutive days and then were maintained drug-free for 14 days to evaluate the reversibility of any observed effects. At the conclusion of each study the animals were sacrificed, the liver removed, weighed and the microsomal subcellular fraction prepared. The hepatic microsomal fraction was then evaluated for protein content, cytochrome P450, and the activities of aniline hydroxylase, aminopyrine N-demethylase, ethoxycoumarin O-deethylase and p-nitrophenol UDP-glucuronosyltransferase. Risedronate was well tolerated during the dosing phase of the study as evidenced by clinical observations, body weight gain and food consumption which were not significantly different from the vehicle controls. Risedronate did not significantly increase (P > 0.05) liver weight, liver/body weight ratio, protein content, P450, aniline hydroxylase, aminopyrine N-demethylase, ethoxycoumarin O-deethylase or p-nitrophenol UDP-glucuronosyltransferase in rats of either sex when compared to vehicle controls. As expected, the hepatic microsomal enzyme inducer phenobarbital significantly increased (P < 0.05) liver weight, liver/body weight ratio, protein content (males only), P450, aniline hydroxylase (males only), aminopyrine N-demethylase (males only), ethoxycoumarin O-deethylase and p-nitrophenol UDP-glucuronosyltransferase in rats relative to vehicle controls. Following the 14 day drug-free recovery period the induction parameters increased by phenobarbital reversed to vehicle control levels. The results obtained in this well controlled study indicate that risedronate is not an inducer of hepatic microsomal drug metabolizing enzymes in the rat.

Effect of bleeding site on clinical laboratory testing of rats: orbital venous plexus versus posterior vena cava.

We sought to determine if there were any differences in the results of clinical laboratory tests between blood samples collected from the orbital venous plexus and the posterior vena cava of adult male rats. Thirty healthy adult male Sprague Dawley rats were anesthetized by ether inhalation, and blood samples were collected successively from the orbital venous plexus (OVP) and the posterior vena cava (PVC) for hematologic (n = 10), serum chemistry (n = 10), and coagulation (n = 10) analyses. The prothrombin and partial thromboplastin times of samples from the OVP were prolonged (17% and 288%, respectively) when compared with samples from the PVC. Respective hematologic biases were as follows: red blood cell count (7%), hemoglobin (6%), hematocrit (5%), mean corpuscular volume (-3%), mean corpuscular hemoglobin (-1%), mean corpuscular hemoglobin content (1%), white blood cell count (13%), and platelet count (-7%). Respective serum chemistry biases were as follows: sorbitol dehydrogenase (-7%), glucose (-7%), blood urea nitrogen (-10%), creatinine (-2%), total protein (4%), albumin (2%), globulin (9%), alkaline phosphatase (5%), lactate dehydrogenase (-6%), aspartate aminotransferase (-5%), alanine aminotransferase (-2%), total bilirubin (0%), direct bilirubin (0%), magnesium (-17%), sodium (4%), potassium (0), chloride (4%), calcium (-2%), phosphorous (-17%), cholesterol (3%), triglycerides (24%), creatinine kinase (-8%), 5'nucleotidase (0%), and total bile acids (4%). For hematologic testing, there were no biologically significant differences between samples collected from the OVP and PVC. The coagulation times and serum Mg and P showed biologically significant differences between samples collected from the OVP and PVC.(ABSTRACT TRUNCATED AT 250 WORDS)