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Studies to characterize pharmacokine...

Kumar, Atul.

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Studies to characterize pharmacokinetic profiles of dextromethorphan, flurbiprofen, midazolam, tiletamine and zolazepam in pigs and to elucidate effect of hemorrhagic shock on cytochrome P450 activities.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Studies to characterize pharmacokinetic profiles of dextromethorphan, flurbiprofen, midazolam, tiletamine and zolazepam in pigs and to elucidate effect of hemorrhagic shock on cytochrome P450 activities./
Author:	Kumar, Atul.
Description:	188 p.
Notes:	Adviser: Henry J. Mann.
Contained By:	Dissertation Abstracts International68-11B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3287820
ISBN:	9780549308355

Studies to characterize pharmacokinetic profiles of dextromethorphan, flurbiprofen, midazolam, tiletamine and zolazepam in pigs and to elucidate effect of hemorrhagic shock on cytochrome P450 activities.
Kumar, Atul.

Studies to characterize pharmacokinetic profiles of dextromethorphan, flurbiprofen, midazolam, tiletamine and zolazepam in pigs and to elucidate effect of hemorrhagic shock on cytochrome P450 activities. - 188 p.

Adviser: Henry J. Mann.

Thesis (Ph.D.)--University of Minnesota, 2007.

The cytochrome P450 (CYP) group of enzymes is responsible for metabolism of most drugs. That a variety of infectious and hypoxic conditions can decrease the expression and activity of CYP enzymes is well established. However, the specific effect of resuscitated hemorrhagic shock on CYP-mediated drug metabolism in-vivo is largely unknown. The first set of experiments comprising this thesis investigated the effect of hemorrhagic shock on cytochrome P450 mediated drug metabolism. The pharmacokinetics of 3 specific CYP probe substrates---dextromethorphan, flurbiprofen and midazolam (selective probes of CYP2D, 2C, and 3A activities; doses 0.5, 0.25 and 0.5 mg/kg IV respectively) were compared in pigs in healthy and in the resuscitative phase of experimental hemorrhagic-shock states. A novel simultaneous assay for dextromethorphan, flurbiprofen and midazolam and their major metabolites was also developed. A highly variable and nonsignificant effect on the clearances of the 3 probes was seen in the resuscitative phase of hemorrhagic shock. Formation of metabolites of probe substrates was seen in large quantities but the same were cleared more slowly from plasma in the post-hemorrhagic shock resuscitation period compared to the healthy phase. This study suggests that the liver retains its drug metabolizing capacity in the resuscitative phase of hemorrhagic shock.

ISBN: 9780549308355Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Studies to characterize pharmacokinetic profiles of dextromethorphan, flurbiprofen, midazolam, tiletamine and zolazepam in pigs and to elucidate effect of hemorrhagic shock on cytochrome P450 activities.
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035 $a (UMI)AAI3287820
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100 1 $a Kumar, Atul. $3 1270498
245 1 0 $a Studies to characterize pharmacokinetic profiles of dextromethorphan, flurbiprofen, midazolam, tiletamine and zolazepam in pigs and to elucidate effect of hemorrhagic shock on cytochrome P450 activities.
300 $a 188 p.
500 $a Adviser: Henry J. Mann.
500 $a Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7271.
502 $a Thesis (Ph.D.)--University of Minnesota, 2007.
520 $a The cytochrome P450 (CYP) group of enzymes is responsible for metabolism of most drugs. That a variety of infectious and hypoxic conditions can decrease the expression and activity of CYP enzymes is well established. However, the specific effect of resuscitated hemorrhagic shock on CYP-mediated drug metabolism in-vivo is largely unknown. The first set of experiments comprising this thesis investigated the effect of hemorrhagic shock on cytochrome P450 mediated drug metabolism. The pharmacokinetics of 3 specific CYP probe substrates---dextromethorphan, flurbiprofen and midazolam (selective probes of CYP2D, 2C, and 3A activities; doses 0.5, 0.25 and 0.5 mg/kg IV respectively) were compared in pigs in healthy and in the resuscitative phase of experimental hemorrhagic-shock states. A novel simultaneous assay for dextromethorphan, flurbiprofen and midazolam and their major metabolites was also developed. A highly variable and nonsignificant effect on the clearances of the 3 probes was seen in the resuscitative phase of hemorrhagic shock. Formation of metabolites of probe substrates was seen in large quantities but the same were cleared more slowly from plasma in the post-hemorrhagic shock resuscitation period compared to the healthy phase. This study suggests that the liver retains its drug metabolizing capacity in the resuscitative phase of hemorrhagic shock.
520 $a The second project described in this thesis to develop a sensitive GC/MS-based analytical method for tiletamine and zolazepam for subsequent use in determining their pharmacokinetics in pigs. An equal weight (1:1 ratio) combination of these two compounds is available commercially as TelazolRTM. Despite the routine use of this product in veterinary practice for the purpose of anesthesia, little information is available on the pharmacokinetics of these 2 compounds. The GC/MS assay was used to analyze plasma samples collected from pigs undergoing minimally invasive surgical procedures after intramuscular administration of 10 mg/kg of TelazolRTM. The pharmacokinetic profiles of tiletamine and zolazepam in pigs were found to differ markedly; zolazepam produced significantly higher average peak concentrations (3.07 vs. 1.02 mug/ml for tiletamine) indicating higher bioavailability after intramuscular administration. The average concentration of zolazepam at the last sampling point (4-6 hours post-administration) was higher than tiletamine indicating slower clearance.
590 $a School code: 0130.
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
710 2 $a University of Minnesota. $3 676231
773 0 $t Dissertation Abstracts International $g 68-11B.
790 $a 0130
790 1 0 $a Mann, Henry J., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3287820