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Br J Clin Pharmacol. 2008 May;65(5):708-15. doi: 10.1111/j.1365-2125.2007.03078.x. Epub 2008 Feb 12.

Time course of the increase in 4beta-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy.

Author information

1
Division of Paediatrics, Department of Clinical Sciences, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:

CYP3A4 converts cholesterol into 4beta-hydroxycholesterol. We have suggested that 4beta-hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments. The kinetics of 4beta-hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4beta-hydroxycholesterol can be used as a CYP3A marker.

WHAT THIS STUDY ADDS:

The concentration of 4beta-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 4beta-hydroxycholesterol levels continued to increase until at least 8 weeks of treatment. AIMS To investigate the time course of the increase in 4beta-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 4beta-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 4beta-hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml(-1). Carbamazepine treatment increased mean plasma 4beta-hydroxycholesterol significantly already after 1 week of treatment (from 43 to 80 ng ml(-1), P < 0.001). 4beta-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 4beta-hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1-2 weeks, the increase in 4beta-hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4beta-hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.

PMID:
18279471
PMCID:
PMC2432481
DOI:
10.1111/j.1365-2125.2007.03078.x
[Indexed for MEDLINE]
Free PMC Article

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