Preclinical Development for clevidipine

Preclinical Development for Clevidipine Name: Institution: Pharmacokinetics & Toxicity Hypertension also referred to as high blood pressure is one of the leading causes of death in the world. The sudden surge of blood pressure damages organs such as the heart. According to the World Health Organization (WHO), hypertension is the second leading cause of fatalities in the world after Cancer. In the U.S, the chronic illness affects over 72 million people who are over 20 years of age. Clevidipine is a U.S drug used in the reduction of blood pressure in patients. The drug is highly effective in controlling acute cases of elevated blood pressure as compared to nitroglycerin and sodium nitroprusside as far as perioperative setting is concerned. Clevidipine is also very effective in patients suffering from acute hypertension. In fact, data shows that the drug is recommended for patients who can only ingest medication intravenously. This characteristic makes the clevidipine the recommended option for patients with hypertensive emergency cases and those undergoing cardiac surgery. This part of the essay shall delve into the use of clevidipine in animals and tissues as part of the pre-clinical development. In pre-clinical developments, major studies were conducted on rats and dogs, as well as limited studies on rabbits. These species aided scientists in making observations on pharmacology, toxicity, metabolism and reproduction studies. The studies involved IV infusion of clevidipine at H152/81 levels in the blood arteries, and the following deductions made. Firstly, clevidipine has linear pharmacokinetics with a short half-life in all species used in the study. It reaches Css levels within 2-5 minutes from the time it is administered intravenously. Finally, clevidipine has the same pharmacokinetics in both male and female species. The blood clearance rates in rabbits, rats and dogs were significantly higher than blood rates, which show that clevidipine has a high hepatic clearance. In addition, the female rats showed a longer half- life for clevidipine due to their significantly lower metabolism as compared to their male counterparts. Repeat doses also increased the rate of clevidipine absorption in dogs. For dogs dosed 12 hours in a day at 50 nmol/kg/min, the hydrolysis of the drug increased to 1.35 minutes from 0.73 between day 1 and 28. The studies revealed that clevidipine had a 99% binding to plasma in all species. The volume of distribution in rats stood at 0.45L while that of rabbits was at 0.17L/kg and 2L/kg in dogs. However, after the administration of the drug, there were high levels of radioactivity experienced in the species within 5 minutes. These were experienced in the blood, the lungs, myocardium, adrenal medulla, the cortex, the tongue, diaphragm, brown fat and the dental pulp. Between 4-16 hours after administering the dosage, H levels in tissues was at a decline. Unusually high levels were evident in urine and the intestines. Some tissues showed high levels of C, which included the vascular organs, excretory organs, secretory organs and the endocrine. C levels also drastically reduced in tissues between 24 and 72 hours of drug administration. Clevidipine was excreted through feces in both dogs and rats. Biliary elimination accounted for 55-70% of the excretion of clevidipine from the body. M5 oxidation product was present in both dog and rat feces. There was also little excretion of unprocessed clevidipine in both species. Excretion occurred within 72 hours of the drug administration. Acute toxicity was experienced in both mice and rats species in the experiment. In mice, a dose of 310 umol/kg or 140mg/kg was the established to be the maximum non-fatal dose. Beyond the 380 umol/kg or 180 mg/kg, death occurred immediately after dosing. The maximum non-fatal dose in male rats was 240 umol/kg or 110 mg/kg. Death occurred at 280 umol/kg or 130 mg/kg. Female rats were more susceptible to clevidipine as death was registered at 200 umol/kg or 91 mg/kg. Repeat dosing was administered to the species for 12-24 hours a day for 4 weeks and the following deductions were made. For rats dosed at 100 nmol/kg/min, no mortalities reported. However, there were changes observed in the rats such as reduced food consumption and increased organ weight. Similar observations were made on dogs. Several deductions were made as far as genetics in the species is concerned. Clevidipine does induce mutation through formaldehyde and other metabolites. The metabolism of drug clevidipine produces some mutagen that cannot easily removed by FDH. Due to the short-term use of the drug, no carcinogenicity studies were feasible. Carcinogenicity studies conducted on calcium channel blockers have not supported evidence of carcinogenic potential in such compounds. In reproductive and developmental toxicity, there were no effects with regards to fertility, mating performance and embryo development in male rats. This was after the rats had been subjected to a dosage of 55 mg/kg/day for 28 days before clevidipine was administered. A similar observation was also made for female rats that were subjected to the same dosage 14 days before the drug was administered. However, in pregnant rodents, there was increased mortality and the length of gestation was prolonged. Formulation & Dosage Clevidipine is similar to felodipine, which is also another calcium inhibitor. However, the structure of the two dihydropyridine is different in that the clevidipine contains an extra ester bond. The hydrolysis of the extra bond is what allows clevidipine be rapidly metabolized in the blood. Clevidipine is also a race mixture of two enantiomers, the S- and R-clevidipine. The drug is oil soluble and not soluble in water because it is manufactured by lipids, which contain egg yolk, glycerin and soybean oil. As a result, the drug is administered in a 20% lipid emulsion solution because of its oil solubility. It has a molecular weight of 456.3 g/m...