QSAR model for human pregnane X receptor (PXR) binding: screening of environmental chemicals and correlations with genotoxicity, endocrine disruption and teratogenicity.

The pregnane X receptor (PXR) has a key role in regulating the metabolism and transport of structurally diverse endogenous and exogenous compounds. Activation of PXR has the potential to initiate adverse effects, causing drug-drug interactions, and perturbing normal physiological functions. Therefore, identification of PXR ligands would be valuable information for pharmaceutical and toxicological research. In the present study, we developed a quantitative structure-activity relationship (QSAR) model for the identification of PXR ligands using data based on a human PXR binding assay. A total of 631 molecules, representing a variety of chemical structures, constituted the training set of the model. Cross-validation of the model showed a sensitivity of 82%, a specificity of 85%, and a concordance of 84%. The developed model provided knowledge about molecular descriptors that may influence the binding of molecules to PXR. The model was used to screen a large inventory of environmental chemicals, of which 47% was found to be within domain of the model. Approximately 35% of the chemicals within domain were predicted to be PXR ligands. The predicted PXR ligands were found to be overrepresented among chemicals predicted to cause adverse effects, such as genotoxicity, teratogenicity, estrogen receptor activation and androgen receptor antagonism compared to chemicals not causing these effects. The developed model may be useful as a tool for predicting potential PXR ligands and for providing mechanistic information of toxic effects of chemicals.

[Analysis and evaluation of the impurity of felodipine and its tablets].

The paper reports the systematic study on felodipine and its impurities in tablets, to improve its quality standards for the control of the related substances. HPLC-DAD, UPLC-MS, IR and NMR methods were used for the isolation of felodipine and its impurities in tablets, their identification and the zebrafish animal model was used for the analysis of the toxic impurities. In felodipine material and its tablets, three impurities are isolated and identified. They are impurity 1 [dimethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate], impurity 2 [ethyl methyl 4-(2, 3-dichlorophenyl)-2, 6-dimethylpyridine-3, 5-dicarboxylate] and impurity 3 [diethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate], separately. The result of zebrafish animal model analysis showed that the teratogenic effects of four compounds were: impurity 3 > or = felodipine > impurity 1 > impurity 2, lethal effects were as follows: impurity 2 = impurity 3 > felodipine > or = impurity 1. This study confirmed the toxicity of three impurities in felodipine. According to the results, the paper suggested the amendments to the standard of the medicine and provided the support to the control of impurities in the manufacturing process.

Felodipine- and ethanol-induced gastric mucosal damage in rats.

Calcium channel blockers like verapamil have been shown to potentiate ethanol-induced gastric mucosal damage. However, the exact mechanism for this adverse drug interaction is still unknown. We used felodipine to study the ulcerogenic mechanisms of calcium channel blockers and the pathogenesis of ethanol-induced ulceration. The experiment was conducted in an ex vivo gastric chamber prepared in anesthetized animals. Felodipine (0.25, 0.5, 1.0, or 2.0 mg/kg s.c.) dose-dependently reduced the systemic blood pressure which was accompanied by a decrease in gastric mucosal blood flow (GMBF), with an insignificant change in heart rate. Ethanol lowered the GMBF and produced gastric mucosal lesions, and these actions were potentiated by felodipine. Preincubation with calcium gluconate but not the sodium salt attenuated the adverse effects of ethanol on GMBF and lesion formation; it also significantly prevented the gastric effects of felodipine but not the decrease of the systemic blood pressure. It is concluded that felodipine aggravates ethanol ulceration through a depressive action on the GMBF. These actions were attenuated by the supplementation with calcium ions in the gastric mucosa. Therefore, maintenance of calcium homeostasis in the gastric wall could play a significant role in the prevention of ethanol ulceration in rats.

General toxicity of the new calcium antagonist felodipine in dogs.

Felodipine 4-(2,3-dichlorophenyl)-1,4-dihydropyridine-2,6-dimethyl-3,5- dicarboxylic 3-ethyl ester and 5-methyl ester, CAS 72509-76-3) is a new selective calcium antagonist for use in the management of hypertension or other cardiovascular disease, which requires reduction of peripheral vascular resistance. A combined 6- and 12-month study in dogs has been performed as a part of the preclinical safety program. 30 dogs, 5 males and 5 females per group, were treated with felodipine for 12 months. Additional 18 dogs, 3 males and 3 females per group, were interim-sacrificed after 6-month treatment. The dose levels were 2 x 0.38, 2 x 1.2 and 2 x 2.3 mg/kg daily. Initially, 2 x 3.8 mg/kg/d was used as a high dose. At this dose level 2 animals died preterminally after 4 days of dosing. They were replaced and the high dose level was reduced. Two similar control groups were given a placebo formulation for 12 and 6 months, respectively. All animals were treated b.i.d. using a 4-h time interval. Mucosal hyperemia and tachycardia, as an expression of the vasodilating properties of felodipine, were observed in a somewhat variable but dose-related manner. Noninflammatory gingival hyperplasia, similar to that after treatment with phenytoin and the calcium antagonist nifedipine, occurred with a propensity for the males after 12 months of treatment. Slight-degree gingival hyperplasia was also noted after 6 months of treatment. This change occurred dose- and time related in the medium and high dose groups but was absent in the low dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive toxicity studies of the antihypertensive agent felodipine in the rat.

Felodipine (4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 5-ethyl 3-methyl ester, CAS 72509-76-3), a vascular selective dihydropyridine calcium antagonist, was tested in three different reproduction studies in the rat. In fertility, teratology and peri-postnatal studies Sprague-Dawley rats were dosed by gavage with 10, 25 and 70 mumol/kg (fertility and teratology studies) or 3, 10 and 30 mumol/kg (peri-postnatal study). There were no increased incidences of external, visceral or skeletal malformations in the teratology study in groups treated with felodipine during organogenesis, compared with the control group. In the fertility and peri-postnatal studies, prolonged parturition and increased incidences of stillborn fetuses and postnatal death were observed in groups given 10 mumol/kg or more, but not at 3 mumol/kg. Similar to the findings in this study, nifedipine, nitrendipine, nicardipine, diltiazem and isradipine have all been reported to induce increased incidences of perinatal death in offsprings in peri-postnatal studies. Thus, the increased incidences of perinatal death (most likely secondary to inhibition of the uterine activity) seems to be a class effect common to all calcium antagonists.