Drug metabolism in hemorrhagic shock: Pharmacokinetics of selective markers of cytochrome-P450 2C9, 2D6, and 3A4 enzyme activities in a porcine model

Atul Kumar, Rory P Remmel, Henry J. Mann, Gregory J Beilman

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Abstract

Background: Cytochrome-P450 enzymes metabolize most administered drugs. A variety of clinical conditions affect the CYP system. However, the effect of hemorrhagic shock on CYP-mediated drug metabolism in clinical setting or in clinically applicable in-vivo models is largely unknown. Simultaneous administration of multiple CYP enzyme-selective drugs is a technique to ascertain a population's metabolic profile with a limited number of subjects. Materials and Methods: Pigs were used as experimental animals as they possess CYP functionality similar to humans. Three probe drugs (dextromethorphan [CYP2D6], flurbiprofen [CYP2C9], and midazolam [CYP3A4]; doses: 0.5, 0.25, and 0.5 mg/kg, respectively) were administered intravenously to six Yorkshire-crossbred pigs in healthy state. Hemorrhagic shock was induced in six (four from healthy group after a 7-d washout period and two additional) pigs and the same doses of probe drugs were administered after a 14-h resuscitation phase. Blood samples were collected periodically in both phases and analyzed for parent drugs and metabolites (dextrorphan, 4'-hydroxy-flurbiprofen and 1'-hydroxy-midazolam) to calculate pharmacokinetic parameters. A comprehensive set of biochemical and physiologic markers of shock was also recorded. Results: No changes in parent drug clearances were observed post-shock. Extensive metabolite formation with apparent higher exposure to total (conjugated and unconjugated) dextrorphan (p = 0.08), 4'-hydroxy-flurbiprofen (p = 0.11) and 1'-hydroxy-midazolam (p = 0.09) were observed post-shock. Conclusions: The metabolic capacity of CYP enzymes did not appear to be severely hindered in resuscitative phase of hemorrhagic shock. Diminished renal secretory function caused by hemorrhagic shock may be the cause of metabolite accumulation in plasma.

Original languageEnglish (US)
JournalJournal of Surgical Research
Volume167
Issue number2
DOIs
StatePublished - May 15 2011

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Cytochrome P-450 CYP3A
Cytochrome P-450 CYP2D6
Hemorrhagic Shock
Swine
Pharmacokinetics
Flurbiprofen
Enzymes
Midazolam
Pharmaceutical Preparations
Dextrorphan
Shock
Cytochrome P-450 Enzyme System
Dextromethorphan
Metabolome
Resuscitation
Biomarkers
Kidney
Population

Keywords

  • cytochrome-P450
  • dextromethorphan
  • flurbiprofen
  • glucuronide
  • midazolam
  • pharmacokinetics
  • physiology
  • pig
  • resuscitation
  • shock

Cite this

@article{5165340b2f2e466fa3da195eafd79bd8,
title = "Drug metabolism in hemorrhagic shock: Pharmacokinetics of selective markers of cytochrome-P450 2C9, 2D6, and 3A4 enzyme activities in a porcine model",
abstract = "Background: Cytochrome-P450 enzymes metabolize most administered drugs. A variety of clinical conditions affect the CYP system. However, the effect of hemorrhagic shock on CYP-mediated drug metabolism in clinical setting or in clinically applicable in-vivo models is largely unknown. Simultaneous administration of multiple CYP enzyme-selective drugs is a technique to ascertain a population's metabolic profile with a limited number of subjects. Materials and Methods: Pigs were used as experimental animals as they possess CYP functionality similar to humans. Three probe drugs (dextromethorphan [CYP2D6], flurbiprofen [CYP2C9], and midazolam [CYP3A4]; doses: 0.5, 0.25, and 0.5 mg/kg, respectively) were administered intravenously to six Yorkshire-crossbred pigs in healthy state. Hemorrhagic shock was induced in six (four from healthy group after a 7-d washout period and two additional) pigs and the same doses of probe drugs were administered after a 14-h resuscitation phase. Blood samples were collected periodically in both phases and analyzed for parent drugs and metabolites (dextrorphan, 4'-hydroxy-flurbiprofen and 1'-hydroxy-midazolam) to calculate pharmacokinetic parameters. A comprehensive set of biochemical and physiologic markers of shock was also recorded. Results: No changes in parent drug clearances were observed post-shock. Extensive metabolite formation with apparent higher exposure to total (conjugated and unconjugated) dextrorphan (p = 0.08), 4'-hydroxy-flurbiprofen (p = 0.11) and 1'-hydroxy-midazolam (p = 0.09) were observed post-shock. Conclusions: The metabolic capacity of CYP enzymes did not appear to be severely hindered in resuscitative phase of hemorrhagic shock. Diminished renal secretory function caused by hemorrhagic shock may be the cause of metabolite accumulation in plasma.",
keywords = "cytochrome-P450, dextromethorphan, flurbiprofen, glucuronide, midazolam, pharmacokinetics, physiology, pig, resuscitation, shock",
author = "Atul Kumar and Remmel, {Rory P} and Mann, {Henry J.} and Beilman, {Gregory J}",
year = "2011",
month = "5",
day = "15",
doi = "10.1016/j.jss.2010.06.040",
language = "English (US)",
volume = "167",
journal = "Journal of Surgical Research",
issn = "0022-4804",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Drug metabolism in hemorrhagic shock

T2 - Pharmacokinetics of selective markers of cytochrome-P450 2C9, 2D6, and 3A4 enzyme activities in a porcine model

AU - Kumar, Atul

AU - Remmel, Rory P

AU - Mann, Henry J.

AU - Beilman, Gregory J

PY - 2011/5/15

Y1 - 2011/5/15

N2 - Background: Cytochrome-P450 enzymes metabolize most administered drugs. A variety of clinical conditions affect the CYP system. However, the effect of hemorrhagic shock on CYP-mediated drug metabolism in clinical setting or in clinically applicable in-vivo models is largely unknown. Simultaneous administration of multiple CYP enzyme-selective drugs is a technique to ascertain a population's metabolic profile with a limited number of subjects. Materials and Methods: Pigs were used as experimental animals as they possess CYP functionality similar to humans. Three probe drugs (dextromethorphan [CYP2D6], flurbiprofen [CYP2C9], and midazolam [CYP3A4]; doses: 0.5, 0.25, and 0.5 mg/kg, respectively) were administered intravenously to six Yorkshire-crossbred pigs in healthy state. Hemorrhagic shock was induced in six (four from healthy group after a 7-d washout period and two additional) pigs and the same doses of probe drugs were administered after a 14-h resuscitation phase. Blood samples were collected periodically in both phases and analyzed for parent drugs and metabolites (dextrorphan, 4'-hydroxy-flurbiprofen and 1'-hydroxy-midazolam) to calculate pharmacokinetic parameters. A comprehensive set of biochemical and physiologic markers of shock was also recorded. Results: No changes in parent drug clearances were observed post-shock. Extensive metabolite formation with apparent higher exposure to total (conjugated and unconjugated) dextrorphan (p = 0.08), 4'-hydroxy-flurbiprofen (p = 0.11) and 1'-hydroxy-midazolam (p = 0.09) were observed post-shock. Conclusions: The metabolic capacity of CYP enzymes did not appear to be severely hindered in resuscitative phase of hemorrhagic shock. Diminished renal secretory function caused by hemorrhagic shock may be the cause of metabolite accumulation in plasma.

AB - Background: Cytochrome-P450 enzymes metabolize most administered drugs. A variety of clinical conditions affect the CYP system. However, the effect of hemorrhagic shock on CYP-mediated drug metabolism in clinical setting or in clinically applicable in-vivo models is largely unknown. Simultaneous administration of multiple CYP enzyme-selective drugs is a technique to ascertain a population's metabolic profile with a limited number of subjects. Materials and Methods: Pigs were used as experimental animals as they possess CYP functionality similar to humans. Three probe drugs (dextromethorphan [CYP2D6], flurbiprofen [CYP2C9], and midazolam [CYP3A4]; doses: 0.5, 0.25, and 0.5 mg/kg, respectively) were administered intravenously to six Yorkshire-crossbred pigs in healthy state. Hemorrhagic shock was induced in six (four from healthy group after a 7-d washout period and two additional) pigs and the same doses of probe drugs were administered after a 14-h resuscitation phase. Blood samples were collected periodically in both phases and analyzed for parent drugs and metabolites (dextrorphan, 4'-hydroxy-flurbiprofen and 1'-hydroxy-midazolam) to calculate pharmacokinetic parameters. A comprehensive set of biochemical and physiologic markers of shock was also recorded. Results: No changes in parent drug clearances were observed post-shock. Extensive metabolite formation with apparent higher exposure to total (conjugated and unconjugated) dextrorphan (p = 0.08), 4'-hydroxy-flurbiprofen (p = 0.11) and 1'-hydroxy-midazolam (p = 0.09) were observed post-shock. Conclusions: The metabolic capacity of CYP enzymes did not appear to be severely hindered in resuscitative phase of hemorrhagic shock. Diminished renal secretory function caused by hemorrhagic shock may be the cause of metabolite accumulation in plasma.

KW - cytochrome-P450

KW - dextromethorphan

KW - flurbiprofen

KW - glucuronide

KW - midazolam

KW - pharmacokinetics

KW - physiology

KW - pig

KW - resuscitation

KW - shock

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U2 - 10.1016/j.jss.2010.06.040

DO - 10.1016/j.jss.2010.06.040

M3 - Article

C2 - 20850770

AN - SCOPUS:79954570089

VL - 167

JO - Journal of Surgical Research

JF - Journal of Surgical Research

SN - 0022-4804

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