Acute hypoxia and cytochrome P450-mediated hepatic drug metabolism in humans

Gesche Jürgens, Hanne Rolighed Christensen, Kim Brøsen, Jesper Sonne, Steffen Loft, Niels Vidiendal Olsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

OBJECTIVE: Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.

METHODS: Twelve healthy subjects who lived at sea level were exposed to altitude-induced hypoxia for 7 days at 4559 m above sea level. Hepatic CYP enzyme activity was measured before departure, at 24 and 96 hours after arrival to high-altitude location, and at 1 month after return to sea level. CYP enzyme activities were measured by means of the metabolic ratios of sparteine (CYP2D6), endogenous cortisol metabolism (CYP3A4), and caffeine (CYP1A2), as well as by the S/R ratio of mephenytoin (CYP2C19) and antipyrine clearance.

RESULTS: The metabolic ratio of sparteine increased after 24 hours at high altitude (median difference, 0.15; 95% confidence interval, 0.05 to 0.28) and remained increased after 96 hours. The ratio decreased after return to sea level (median difference, -0.15; 95% confidence interval, -0.29 to -0.03; P =.016, Friedman test). The metabolic ratio of cortisol decreased after 24 hours (median difference, -2.0; 95% confidence interval, -3.5 to -0.5) but returned to sea level values after 96 hours at high altitude (median difference, 1.6; 95% confidence interval, 1.0 to 4.2; P =.047, Friedman test). These changes indicate a small decrease in the activity of CYP2D6 and CYP3A4. There were no significant changes regarding the metabolic ratio of caffeine, the S/R ratio of mephenytoin, or antipyrine clearance.

CONCLUSION: The small changes observed suggest that acute hypoxia has no clinically significant effects on CYP enzymes in humans.

OriginalsprogEngelsk
TidsskriftClinical Pharmacology and Therapeutics
Vol/bind71
Udgave nummer4
Sider (fra-til)214-20
Antal sider7
ISSN0009-9236
DOI
StatusUdgivet - 2002

Fingeraftryk

Cytochrome P-450 Enzyme System
Liver
Pharmaceutical Preparations
Mephenytoin
Confidence Intervals
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP2D6
Altitude Sickness
Cytochrome P-450 CYP1A2

Emneord

  • Acute Disease
  • Adult
  • Altitude
  • Anoxia
  • Caffeine
  • Cytochrome P-450 Enzyme System
  • Female
  • Humans
  • Hydrocortisone
  • Liver
  • Longitudinal Studies
  • Male
  • Mephenytoin
  • Sparteine
  • Statistics, Nonparametric

Citer dette

Jürgens, Gesche ; Christensen, Hanne Rolighed ; Brøsen, Kim ; Sonne, Jesper ; Loft, Steffen ; Olsen, Niels Vidiendal. / Acute hypoxia and cytochrome P450-mediated hepatic drug metabolism in humans. I: Clinical Pharmacology and Therapeutics. 2002 ; Bind 71, Nr. 4. s. 214-20.
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abstract = "OBJECTIVE: Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.METHODS: Twelve healthy subjects who lived at sea level were exposed to altitude-induced hypoxia for 7 days at 4559 m above sea level. Hepatic CYP enzyme activity was measured before departure, at 24 and 96 hours after arrival to high-altitude location, and at 1 month after return to sea level. CYP enzyme activities were measured by means of the metabolic ratios of sparteine (CYP2D6), endogenous cortisol metabolism (CYP3A4), and caffeine (CYP1A2), as well as by the S/R ratio of mephenytoin (CYP2C19) and antipyrine clearance.RESULTS: The metabolic ratio of sparteine increased after 24 hours at high altitude (median difference, 0.15; 95{\%} confidence interval, 0.05 to 0.28) and remained increased after 96 hours. The ratio decreased after return to sea level (median difference, -0.15; 95{\%} confidence interval, -0.29 to -0.03; P =.016, Friedman test). The metabolic ratio of cortisol decreased after 24 hours (median difference, -2.0; 95{\%} confidence interval, -3.5 to -0.5) but returned to sea level values after 96 hours at high altitude (median difference, 1.6; 95{\%} confidence interval, 1.0 to 4.2; P =.047, Friedman test). These changes indicate a small decrease in the activity of CYP2D6 and CYP3A4. There were no significant changes regarding the metabolic ratio of caffeine, the S/R ratio of mephenytoin, or antipyrine clearance.CONCLUSION: The small changes observed suggest that acute hypoxia has no clinically significant effects on CYP enzymes in humans.",
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author = "Gesche J{\"u}rgens and Christensen, {Hanne Rolighed} and Kim Br{\o}sen and Jesper Sonne and Steffen Loft and Olsen, {Niels Vidiendal}",
year = "2002",
doi = "10.1067/mcp.2002.121789",
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Acute hypoxia and cytochrome P450-mediated hepatic drug metabolism in humans. / Jürgens, Gesche; Christensen, Hanne Rolighed; Brøsen, Kim; Sonne, Jesper; Loft, Steffen; Olsen, Niels Vidiendal.

I: Clinical Pharmacology and Therapeutics, Bind 71, Nr. 4, 2002, s. 214-20.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Acute hypoxia and cytochrome P450-mediated hepatic drug metabolism in humans

AU - Jürgens, Gesche

AU - Christensen, Hanne Rolighed

AU - Brøsen, Kim

AU - Sonne, Jesper

AU - Loft, Steffen

AU - Olsen, Niels Vidiendal

PY - 2002

Y1 - 2002

N2 - OBJECTIVE: Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.METHODS: Twelve healthy subjects who lived at sea level were exposed to altitude-induced hypoxia for 7 days at 4559 m above sea level. Hepatic CYP enzyme activity was measured before departure, at 24 and 96 hours after arrival to high-altitude location, and at 1 month after return to sea level. CYP enzyme activities were measured by means of the metabolic ratios of sparteine (CYP2D6), endogenous cortisol metabolism (CYP3A4), and caffeine (CYP1A2), as well as by the S/R ratio of mephenytoin (CYP2C19) and antipyrine clearance.RESULTS: The metabolic ratio of sparteine increased after 24 hours at high altitude (median difference, 0.15; 95% confidence interval, 0.05 to 0.28) and remained increased after 96 hours. The ratio decreased after return to sea level (median difference, -0.15; 95% confidence interval, -0.29 to -0.03; P =.016, Friedman test). The metabolic ratio of cortisol decreased after 24 hours (median difference, -2.0; 95% confidence interval, -3.5 to -0.5) but returned to sea level values after 96 hours at high altitude (median difference, 1.6; 95% confidence interval, 1.0 to 4.2; P =.047, Friedman test). These changes indicate a small decrease in the activity of CYP2D6 and CYP3A4. There were no significant changes regarding the metabolic ratio of caffeine, the S/R ratio of mephenytoin, or antipyrine clearance.CONCLUSION: The small changes observed suggest that acute hypoxia has no clinically significant effects on CYP enzymes in humans.

AB - OBJECTIVE: Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.METHODS: Twelve healthy subjects who lived at sea level were exposed to altitude-induced hypoxia for 7 days at 4559 m above sea level. Hepatic CYP enzyme activity was measured before departure, at 24 and 96 hours after arrival to high-altitude location, and at 1 month after return to sea level. CYP enzyme activities were measured by means of the metabolic ratios of sparteine (CYP2D6), endogenous cortisol metabolism (CYP3A4), and caffeine (CYP1A2), as well as by the S/R ratio of mephenytoin (CYP2C19) and antipyrine clearance.RESULTS: The metabolic ratio of sparteine increased after 24 hours at high altitude (median difference, 0.15; 95% confidence interval, 0.05 to 0.28) and remained increased after 96 hours. The ratio decreased after return to sea level (median difference, -0.15; 95% confidence interval, -0.29 to -0.03; P =.016, Friedman test). The metabolic ratio of cortisol decreased after 24 hours (median difference, -2.0; 95% confidence interval, -3.5 to -0.5) but returned to sea level values after 96 hours at high altitude (median difference, 1.6; 95% confidence interval, 1.0 to 4.2; P =.047, Friedman test). These changes indicate a small decrease in the activity of CYP2D6 and CYP3A4. There were no significant changes regarding the metabolic ratio of caffeine, the S/R ratio of mephenytoin, or antipyrine clearance.CONCLUSION: The small changes observed suggest that acute hypoxia has no clinically significant effects on CYP enzymes in humans.

KW - Acute Disease

KW - Adult

KW - Altitude

KW - Anoxia

KW - Caffeine

KW - Cytochrome P-450 Enzyme System

KW - Female

KW - Humans

KW - Hydrocortisone

KW - Liver

KW - Longitudinal Studies

KW - Male

KW - Mephenytoin

KW - Sparteine

KW - Statistics, Nonparametric

U2 - 10.1067/mcp.2002.121789

DO - 10.1067/mcp.2002.121789

M3 - Journal article

VL - 71

SP - 214

EP - 220

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 4

ER -