TY - JOUR
T1 - PKQuest
T2 - Measurement of intestinal absorption and first pass metabolism - Application to human ethanol pharmacokinetics
AU - Levitt, David G.
PY - 2002/8/15
Y1 - 2002/8/15
N2 - Background: PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose - PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption. Methods: PKQuest was applied to previously published ethanol pharmacokinetic data. Results: The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small. Conclusions: The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at [www.pkquest.com].
AB - Background: PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose - PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption. Methods: PKQuest was applied to previously published ethanol pharmacokinetic data. Results: The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small. Conclusions: The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at [www.pkquest.com].
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U2 - 10.1186/1472-6904-2-4
DO - 10.1186/1472-6904-2-4
M3 - Article
C2 - 12182761
AN - SCOPUS:2342486342
SN - 1472-6904
VL - 2
JO - BMC Clinical Pharmacology
JF - BMC Clinical Pharmacology
M1 - 4
ER -