Time Course of the Increase in 4beta-hydroxycholesterol Concentration During Carbamazepine Treatment of Paediatric Patients with Epilepsy

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2008 Feb 19

PMID 18279471

Citations 12

Authors

Katarina Wide

Hanna Larsson

Leif Bertilsson

Ulf Diczfalusy

Affiliations

Soon will be listed here.

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.

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References

Janowski B, Willy P, Devi T, Falck J, Mangelsdorf D . An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996; 383(6602):728-31. DOI: 10.1038/383728a0. View

Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G, Wahren J . Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res. 1998; 39(8):1594-600. View

Catignani G, BIERI J . Simultaneous determination of retinol and alpha-tocopherol in serum or plasma by liquid chromatography. Clin Chem. 1983; 29(4):708-12. View

Perucca E . Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006; 61(3):246-55. PMC: 1885026. DOI: 10.1111/j.1365-2125.2005.02529.x. View

Tomson T, Svensson J, Hilton-Brown P . Relationship of intraindividual dose to plasma concentration of carbamazepine: indication of dose-dependent induction of metabolism. Ther Drug Monit. 1989; 11(5):533-9. View

Diczfalusy U, Miura J, Roh H, Mirghani R, Sayi J, Larsson H . 4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians. Pharmacogenet Genomics. 2008; 18(3):201-8. DOI: 10.1097/FPC.0b013e3282f50ee9. View

Bodin K, Bretillon L, Aden Y, Bertilsson L, Broome U, Einarsson C . Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J Biol Chem. 2001; 276(42):38685-9. DOI: 10.1074/jbc.M105127200. View

Eichelbaum M, Burk O . CYP3A genetics in drug metabolism. Nat Med. 2001; 7(3):285-7. DOI: 10.1038/85417. View

Babiker A, Andersson O, Lindblom D, van der Linden J, Wiklund B, Lutjohann D . Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. J Lipid Res. 1999; 40(8):1417-25. View

10.

Mirghani R, Ericsson O, Tybring G, Gustafsson L, Bertilsson L . Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man. Eur J Clin Pharmacol. 2003; 59(1):23-8. DOI: 10.1007/s00228-003-0575-5. View

11.

Bertilsson L, Hojer B, Tybring G, Osterloh J, Rane A . Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique. Clin Pharmacol Ther. 1980; 27(1):83-8. DOI: 10.1038/clpt.1980.13. View

12.

Oscarson M, Zanger U, Rifki O, Klein K, Eichelbaum M, Meyer U . Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006; 80(5):440-456. DOI: 10.1016/j.clpt.2006.08.013. View

13.

Moreland T, Park B, Rylance G . Microsomal enzyme induction in children: the influence of carbamazepine treatment on antipyrine kinetics, 6 beta-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity. Br J Clin Pharmacol. 1982; 14(6):861-5. PMC: 1427548. DOI: 10.1111/j.1365-2125.1982.tb02050.x. View

14.

Geick A, Eichelbaum M, Burk O . Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001; 276(18):14581-7. DOI: 10.1074/jbc.M010173200. View

15.

Tomlinson B, Young R, Ng M, Anderson P, Kay R, Critchley J . Selective liver enzyme induction by carbamazepine and phenytoin in Chinese epileptics. Eur J Clin Pharmacol. 1996; 50(5):411-5. DOI: 10.1007/s002280050132. View

16.

Parker R, Sontag T, Swanson J . Cytochrome P4503A-dependent metabolism of tocopherols and inhibition by sesamin. Biochem Biophys Res Commun. 2000; 277(3):531-4. DOI: 10.1006/bbrc.2000.3706. View

17.

Meaney S, Hassan M, Sakinis A, Lutjohann D, von Bergmann K, Wennmalm A . Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study. J Lipid Res. 2001; 42(1):70-8. View

18.

Meaney S, Bodin K, Diczfalusy U, Bjorkhem I . On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function. J Lipid Res. 2002; 43(12):2130-5. DOI: 10.1194/jlr.m200293-jlr200. View

19.

Marschall H, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J . Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 2005; 129(2):476-85. DOI: 10.1016/j.gastro.2005.05.009. View

20.

Mirghani R, Sayi J, Aklillu E, Allqvist A, Jande M, Wennerholm A . CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population. Pharmacogenet Genomics. 2006; 16(9):637-45. DOI: 10.1097/01.fpc.0000230411.89973.1b. View