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dc.contributor.authorMiller, Ann Kay
dc.date.accessioned2013-04-08T15:07:00Z
dc.date.available2013-04-08T15:07:00Z
dc.date.issued1992
dc.identifier.urihttp://hdl.handle.net/10713/2563
dc.descriptionUniversity of Maryland, Baltimore. Pharmacokinetics. Ph.D. 1992en_US
dc.description.abstractN-methylspiperone (NMSP) is a butyrophenone derivative that binds preferentially to dopamine D2 receptors in the brain of animals and man. This dissertation describes the development of a specific and sensitive HPLC assay for quantitation of NMSP in guinea pig plasma and brain. The metabolism of NMSP is studied in guinea pigs and rats after multiple intraperitoneal injections of NMSP. Three important metabolites found in guinea pig plasma and brain were identified as reduced NMSP, spiperone, and reduced spiperone. Only spiperone was found in rats. Furthermore, reduced NMSP was found to be a radiolabeled metabolite after single or multiple doses of {dollar}\sp3{dollar}H-NMSP and after a single dose of {dollar}\sp{lcub}11{rcub}{dollar}C-NMSP in guinea pigs. The plasma disposition of NMSP and {dollar}\sp3{dollar}H-NMSP in guinea pigs after a single intravenous dose was best described by a biexponential decline. The half-lives of NMSP distribution and elimination were 11.7 and 289 minutes, respectively. Reduced NMSP was found to follow a mono- or biexponential decline in plasma after a single intravenous dose. The mean elimination half-life was 54.7 minutes. The "donor-recipient" parameter estimation method was evaluated for usefulness in NMSP receptor binding studies. This method includes estimation of transfer rates of formation of a radiolabeled metabolite in the body and transfer of the metabolite into and out of the brain. Data was simulated for a radiolabeled parent compound and its radiolabeled metabolite in the plasma and in the two types of brain regions--those with and without specific binding of parent to the receptors. All parameters except the rate constant of metabolite elimination from the body were estimated within 1% of the true value. Parameters estimated by non-linear least squares regression analysis were found to be similar to those from the "donor-recipient" method. In evaluating the "donor-recipient" method when specific binding is assumed to be reversible, only K23 was poorly estimated. The "donor-recipient" method does provide accurate estimation of all parameters of interest in the receptor binding models determined in this analysis. However, K23, the rate of sequestration into the brain compartment, is only accurately estimated when it is truly represented by a first order process and K23 is zero. (Abstract shortened with permission of author.)en_US
dc.language.isoen_USen_US
dc.subjectBiology, Neuroscienceen_US
dc.subjectHealth Sciences, Pharmacologyen_US
dc.titleThe evaluation of the metabolism of N-methylspiperone and its effect on kinetic and receptor binding parameter estimationen_US
dc.typedissertationen_US
dc.contributor.advisorYoung, David G. en_US
dc.identifier.ispublishedYes
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