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Time course of the increase in 4β‐hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy
Author(s) -
Wide Katarina,
Larsson Hanna,
Bertilsson Leif,
Diczfalusy Ulf
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.03078.x
Subject(s) - carbamazepine , epilepsy , medicine , anticonvulsant , pharmacology , pediatrics , psychiatry
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP3A4 converts cholesterol into 4β‐hydroxycholesterol. • We have suggested that 4β‐hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments. • The kinetics of 4β‐hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4β‐hydroxycholesterol can be used as a CYP3A marker. WHAT THIS STUDY ADDS • The concentration of 4β‐hydroxycholesterol increases very slowly during CYP3A4/5 induction in paediatric patients. • Whereas induction of CYP3A4/5 was apparently complete within 1–2 weeks of carbamazepine treatment, plasma 4β‐hydroxycholesterol levels continued to increase until at least 8 weeks of treatment. AIMS To investigate the time course of the increase in 4β‐hydroxycholesterol and carbamazepine plasma concentrations during treatment of paediatric patients with epilepsy. METHODS Eight paediatric patients with newly diagnosed epilepsy were studied. Blood samples were drawn before and after about 1, 2, 4, 8 and 16 weeks of carbamazepine treatment. The plasma concentrations of 4β‐hydroxycholesterol were determined by gas chromatography–mass spectrometry and carbamazepine and its epoxide metabolite by high‐performance liquid chromatography. RESULTS The basal plasma concentrations of 4β‐hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml −1 . Carbamazepine treatment increased mean plasma 4β‐hydroxycholesterol significantly already after 1 week of treatment (from 43 to 80 ng ml −1 , P < 0.001). 4β‐Hydroxycholesterol concentrations continued to increase until at least 8 weeks of treatment and the concentrations in the final samples (8–23 weeks of treatment) varied between 122 and 494 ng ml −1 . Plasma concentrations of carbamazepine and its epoxide metabolite reached steady state at 1–2 weeks after last dose change. CONCLUSIONS Carbamazepine treatment of paediatric patients with epilepsy resulted in an induction of CYP3A4/5 and a concomitant increase in plasma 4β‐hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1–2 weeks, the increase in 4β‐hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4β‐hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.