Pharmacodynamics of carbamazepine-mediated induction of CYP3A4, CYP1A2, and Pgp as assessed by probe substrates midazolam, caffeine, and digoxin.
The aim of this study was to develop a model describing the carbamazepine autoinduction and the carbamazepine-mediated induction of CYP3A4, CYP1A2, and P-glycoprotein. Seven healthy volunteers were dosed with carbamazepine over 16 consecutive days. The CYP3A4, CYP1A2, and P-glycoprotein activities were assessed, using midazolam, caffeine, and digoxin as probe substrates, on 12 occasions, covering the preinduced state and the onset and termination of the induction process. The data were evaluated using a mechanistic pharmacokinetic approach in NONMEM. The induction processes were described using turnover models, with carbamazepine and carbamazepine-10,11-epoxide as the driving force of the induction. The half-lives of CYP3A4 and CYP1A2 were estimated to be 70 and 105 h, respectively. P-glycoprotein was not affected by the carbamazepine treatment. The possibility of modeling the pharmacodynamics of enzyme induction using a turnover model was illustrated, and the time course of the process was estimated with good precision.
Magnusson
M O
MO
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Mats.Magnusson@farmbio.uu.se
Dahl
M-L
ML
Cederberg
J
J
Karlsson
M O
MO
Sandström
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000328:Adult; D002110:Caffeine / Q000378:metabolism*; D002220:Carbamazepine / Q000378:metabolism / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004077:Digoxin / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008874:Midazolam / Q000378:metabolism*; D008875:Middle Aged; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002220:Carbamazepine; D002110:Caffeine; D004077:Digoxin; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam