Bioavailability studies of drugs with nonlinear pharmacokinetics: I. Tracer dose AUC varies directly with serum concentration.
The authors show that for a drug cleared by one enzyme the area under the serum concentration-time curve from time 0 to infinity (AUC0-INF) of a test dose can be expressed as AUC0-INF = TD x F x (Km + C)/Vmax where TD is test dose size, F is fraction absorbed, C is drug serum concentration at the time of the study, and Km and Vmax are the Michaelis constant and maximum velocity of the enzyme. This equation predicts the AUC0-INF produced by a given tracer dose of drug will vary directly with C in drugs with nonlinear pharmacokinetic properties (i.e., drugs whose value for C approaches or exceeds Km) if C is held constant by administration of tracer and maintenance doses of drug. The AUC0-INF produced by intravenous tracer doses of 150 mg of 13C15N2-sodium phenytoin was determined in 15 subjects at 30 different values of C. AUC0-INF showed a high degree of direct linear correlation with C (AUC0-INF (ug x hr/mL) = 35.4 + 8.1 x C (ug/mL), r = 0.885, P < .0001). Consequences of this observation for relative bioavailability studies of drugs with nonlinear pharmacokinetic properties are discussed.
Browne
T R
TR
Department of Neurology and Pharmacology, Boston University School of Medicine, MA.
Szabo
G K
GK
Schumacher
G E
GE
Greenblatt
D J
DJ
Evans
J E
JE
Evans
B A
BA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D010672:Phenytoin