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New Pharmacokinetic Methods II: Determination of the Presence or Absence of Product Inhibition in Drugs with Nonlinear Pharmacokinetics
Author(s) -
Browne Thomas R.,
Szabo George K.,
Walsh Carol T.,
Schumacher Gerald E.,
Evans James E.,
Evans Barbara A.
Publication year - 1990
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1990.tb01859.x
Subject(s) - pharmacokinetics , saturation (graph theory) , phenytoin , chemistry , substrate (aquarium) , uncompetitive inhibitor , product inhibition , chromatography , pharmacology , non competitive inhibition , mathematics , enzyme , medicine , biochemistry , biology , epilepsy , ecology , combinatorics , psychiatry
We show that for drugs metabolized by one enzyme the slope of a plot of serum concentration (C) versus 1/clearance (CL) is linear with a value of 1/V max in the presence of substrate saturation and may be linear (rarely) or curved (usually) with a slope always greater than 1/V max in the presence of substrate saturation and product inhibition (competitive, noncompetitive, or uncompetitive) when the serum concentration of product varies with the serum concentration of substrate. Serum concentration, CL, and V max were determined for a group of six subjects receiving phenytoin monotherapy using three approaches. With each approach: 1) a plot C versus 1/CL was linear (r ≥ 0.738, P < .01); 2) the slope of this regression line did not differ significantly ( P > .30) from 1/V max . We conclude: 1) our method is a simple and useful method for determination of mechanism of a drug's nonlinear pharmacokinetics (substrate saturation versus substrate saturation and product inhibition), 2) phenytoin has nonlinear pharmacokinetics due to substrate saturation only in man.