1Assistant Professor, Department of Biochemistry, Santosh University, Ghaziabad, Uttar Pradesh, India
2Professor & Head, Department of Biochemistry, Santosh University, Ghaziabad, Uttar Pradesh, India
3Scholar, Department of Biochemistry, Integral Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
4Scientist, Medicinal Chemistry, Central Drug Research Institute, Lucknow, Uttar Pradesh, India
5Scientist, Pharmacokinetics Division Central Drug Research Institute, Lucknow, Uttar Pradesh, India
*Corresponding author: Preeti Sharma, Assistant Professor, Department of Biochemistry, Santosh University, Ghaziabad, U.P., India, Mob. 09456956187, 09313177768, E-mail: prcdri2003@yahoo.co.in
Online published on 6 November, 2014.
Recent studies which were undertaken at CDRI to study the effect of N- acyl derivatives of various aminoacids, have culminated in the identification of an oxazolidine derivatives 4, 5 cis-5-styryl-2-oxo-oxazolidine-4-carboxylic acid(CDRI 85/92) having good proton pump inhibitory activity. This compound is as potent as omeprazole in in vitro inhibition of H+/K+ ATPase and in various animal models. The compound is undergoing advanced stage of clinical trials. Preclinical pharmacokinetics of oxazolidine derivatives 4, 5 cis-5-styryl-2-oxo-oxazolidine-4- carboxylic acid after a single 20 Mg/Kg oral dose and I. V. administration in male Sprague Dawlay rats showed that the compound is rapidly absorbed. After attaining a peak concentration at 1 hour, it is rapidly eliminated with elimination half life of 2 hours. The clearance of the compound was high. The systemic bioavailability of the compound was more than 60%. This compound is short acting and has to be administered frequently. In an effort to increase the duration of action of the compound, the compound was prepared by capping the carboxylic group of the parent compound with ethyl acetate group, generated the prodrug. The pharmacokinetics of the parent compound, after administration of the prodrug was studied. The concentration of the parent compound from the prodrug in rat serum was determined using the validated HPLC method with gradient elution. The concentration time profile of the parent compound from its prodrug showed rapid absorption with maximum concentration of 956ng/mole at 5 min. The serum concentration time data was subjected to noncompartmental approach using winNonlin software, to determine the pharmacokinetic parameters. The clearance of the compound was reduced to 1/4th as compared to the administration of parent compound, thereby increasing the half-life from 4.3 hours to 17.7 hours which was higher than the parent compound. The compound therefore stays longer in the body and may be effective for a longer period of the time than the parent compound.
Pharmacokinetic studies, CDRI 85/92, HPLC, Prodrug, Antiulcer agent, Proton pump inhibitor
