Metabolic properties of the acid and lactone forms of HMG-CoA reductase inhibitors.

To gain a better understanding of the metabolic properties between the open acid and lactone form of HMG-CoA reductase inhibitors (statins), the paper focused primarily on characterizing the metabolic properties of statins. We compared the metabolism of the acid and lactone forms of several statins, including atrovastatin, simvastatin, cerivastatin fluvastatin, pitavastatin and rosuvastatin with respect to metabolic clearance, CYP enzymes involved and drug-drug interactions. A remarkable increase in metabolic clearance was noted for all lactones compared with all acids except for pitavastatin lactone. The metabolic clearances of the atrovastatin, simvastatin, cerivastatin, fluvastatin and rosuvastatin lactones were 73-, 70-, 30-, 7- and 64-fold higher, respectively, than those of the corresponding acids. CYP2Cs were critically involved in the metabolism of cerivastatin, fluvastatin and pitavastatin acids. In contrast, CYP2Cs were not involved in the metabolism of the corresponding lactones and CYP3A4 was mainly involved. Moreover, a substantial difference in the metabolic inhibition of statins was found between acids and lactones. Overall, the study demonstrates that CYP-mediated metabolism of lactones is also a common metabolic pathway for statins and that the CYP3A4-mediated metabolism of the lactone forms clearly will need to be taken into account in assessing mechanistic aspects of drug-drug interaction involving statins.

Teratogenicity of the antiallergic Sm 857 SE in rats versus rabbits.

Sm 857 SE is an antiallergic drug chemically described as 11-Oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid that has activity against allergic bronchoconstriction in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. The drug was suspended in aqueous 0.25% carboxymethylcellulose (CMC) solution. Daily doses of 20, 90, or 400 mg/kg were given orally by gavage to rats on days 7 through 17 of gestation and to rabbits on days 6 through 18. Two additional studies were done in rats dosed with 400 mg/kg, and with 90, 200, or 400 mg/kg, respectively. Doses of 20, 90, and 200 mg/kg had no meaningful effects on maternal animals of either species or on their offspring. A dose of 400 mg/kg was maternally toxic in rats as shown by the effects on body weight and food consumption. Among pregnant rabbits, two deaths and three miscarriages occurred at this dose. In rats, 400 mg/kg caused embryonic death, retarded fetal development, and two specific malformations, namely microphthalmia and vertebral-costal defects. A mild teratogenic action of 400 mg/kg also occurred in the first additional study but not in the second one. There was, however, one anophthalmia in a rat fetus of the 90 mg/kg group. In rabbits, no embryotoxic or teratogenic effects were observed. These species differences were explained by the concentration and protein binding in maternal serum as well as by the relatively high concentration of 14C-Sm 857 SE in the rat fetus.

Corticosterone induction of cleft palate in mice dosed with orciprenaline sulfate.

Orciprenaline sulfate is a beta-adrenoceptor stimulant chemically described as 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-isopropylaminoethane sulfate (Alupent). The drug has broncho-dilating activity and has been developed in numerous countries since 1961. The purpose of these studies was to investigate the teratogenic potential of orciprenaline and its mode of action in pregnant Jcl:ICR mice, when administered during the period of organogenesis and, more systematically, during the critical period of palate formation. Daily doses of 5, 50, and 500 mg/kg were given orally by gavage to mice on days 6-15, 11-13, or on day 12 of gestation. Additional studies were done to evaluate the maternal cardiotoxic action of orciprenaline and its effects on adrenal cortex and endogenous serum corticosterone. Five mg/kg triamcin-olone acetonide, a glucocorticoid, were given subcutaneously as a positive control causing 100% cleft palate. Myocardial necroses occurred in pregnant mice only after 500 mg/kg orciprenaline had been given, and a significant increase in cleft palate occurred if exposure took place during days 11-13 or day 12 of gestation. This increase in cleft palate can be explained by the teratogenic effect of an elevated maternal serum corticosterone level 1 hr after orciprenaline treatment, about three times the control value.

Cardiac effects of fenoterol hydrobromide on newborn versus adult rats.

The toxicity of fenoterol hydrobromide, a beta-adrenoceptor stimulant, was studied in newborn and adult SD-rats dosed with 0 (control), 2.5, 75 and 600 mg/kg/day by gavage for 35 days. 600 mg/kg was lethal for both age groups: newborn rats died either from gastro-intestinal disorders during the lactation period or from underweight and cachexia immediately after weaning. Adult rats which died from 600 mg/kg showed extended myocardial scars. No substance-related myocardial lesions were observed in newborn rats killed terminally, whereas adult rats had a dose-dependent increase in heart weights, at 600 mg/kg also extended myocardial scars.

Hair embolism in lungs of rat and rabbit caused by intravenous injection.

Among 1422 Sprague-Dawley rats treated daily for 28 consecutive days by i.v. injection, 144 animals (10.1%) showed particles of hair in thrombi at the site of injection. 381 rats (26.8%) had pulmonary emboli with fragments of hair and skin in arterial thrombi or in giant cell granulomas. 6 weeks after cessation of treatment lesions were still found in lungs from 5 of 90 rats (5.6%) allowed to recover. After the experimental administration of 0.75 ml/100 g body wt of a hair suspension (3000 hair particles/ml) to rats, there was no influence on phagocytosis whether endogenous or foreign hairs were injected. In 8 of 64 Himalayan rabbits (12.5%) given 28 injections each into ear veins pulmonary embolism was observed.

Teratology study with orciprenaline sulfate in rabbits.

Orciprenaline sulfate (Alupent), a beta-adrenoceptor stimulant, was studied for adverse effects on pregnant rabbits and their fetuses. Himalayan rabbits (Kawanishi) were dosed orally at 0 (control), 5, 25 and 50 mg/kg/d from gestation day 6 through 18. 15 does were used per group. No distinct influences of orciprenaline sulfate on litter parameters and no teratogenic effect was observed including the "maximum tolerated dose" of 50 mg/kg.

Hair embolism in lungs of rats after intravenous injection into caudal veins.

In case of intravenous injection into caudal veins of rats, the occasional inoculation of hair particles into the lumen of the vein cannot be avoided. These hairs either cause a local thrombophlebitis or are floated with the blood stream until they are thoughout caught by the pulmonary filters, even if they measure less than 10 mu in length. In capillaries or alveoli of lungs phagocytosis by giant cells will start after about 3 days and will be fully terminated within four weeks.