Accession Number : ADA183680

Title :   Alteration of the Efficacy and Toxicity of Clinically Useful Drug Esters by Organophosphate Inhibitors.

Descriptive Note : Annual rept. 30 Mar 84-29 Mar 85,

Corporate Author : EASTERN VIRGINIA MEDICAL SCHOOL NORFOLK DEPT OF PHARMACOLOGY

Personal Author(s) : Castle,Mickey

PDF Url : ADA183680

Report Date : 22 May 1985

Pagination or Media Count : 65

Abstract : The present studies are intended to develop animal models for investigations of the hydrolysis of therapeutically useful drug esters, especially those hydrolized by carboxylesterases. These models were used to investigate the effects of organophosphate compounds on ester hydrolysis in vitro and in vivo. Liver microsomes were isolated from untreated guinea pigs and subsequently incubated with one of several ester substrates (chloramphenicol succinate, prednisolone succinate, procaine, procaineamide, lidocaine, methylparaben and meperidine). Only four of the substrates exhibited significant hydrolysis: Chloramphenicol succinate, prednisolone succinate, procaine, and Methylparaben. The results of these investigations demonstrate that carboxylesterase activity toward several esters of drugs is present in liver, lung and kidney. The liver is by far the most important site of hydrolysis of these ester compounds. Some substrates are hydrolyzed by the lung and kidney to a greater extend than other substrates. The administration of paraoxon, even in high doses, failed to produce a consistent or pronounced inhibition of carboxylesterase activity. In some cases, pretreatment with paraoxon actually increased enzyme activity. These results suggest that paraoxon pretreatment may cause eithet inhibition or enhancement of enzyme activity in the guinea pig.

Descriptors :   *ESTERS, *ESTERASES, *ORGANOPHOSPHATES, *TOXICITY, DRUGS, ENZYMES, ESTERS, GUINEA PIGS, HYDROLYSIS, IN VITRO ANALYSIS, IN VIVO ANALYSIS, INHIBITION, INHIBITORS, INSECTICIDES, LIVER, LOCAL ANESTHETICS, LUNG, MICROSOMES, NITROPHENOLS, OPTIMIZATION, ORGANOPHOSPHATES, PHOSPHATES, TOXICITY, CHEMOTHERAPEUTIC AGENTS, LABORATORY ANIMALS, TABLES(DATA), GRAPHS, KIDNEYS, CARBOXYL GROUPS, CARBOXYLIC ESTER HYDROLASES, METABOLISM

Subject Categories : Pharmacology
      Toxicology
      Biochemistry

Distribution Statement : APPROVED FOR PUBLIC RELEASE