Time course of the increase in 4β‐hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• CYP3A4 converts cholesterol into 4b-hydroxycholesterol.• We have suggested that 4b-hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments.• The kinetics of 4b-hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4b-hydroxycholesterol can be used as a CYP3A marker. WHAT THIS STUDY ADDS• The concentration of 4b-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 4b-hydroxycholesterol levels continued to increase until at least 8 weeks of treatment. AIMSTo investigate the time course of the increase in 4b-hydroxycholesterol and carbamazepine plasma concentrations during treatment of paediatric patients with epilepsy. METHODSEight 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 4b-hydroxycholesterol were determined by gas chromatography-mass spectrometry and carbamazepine and its epoxide metabolite by high-performance liquid chromatography. RESULTSThe basal plasma concentrations of 4b-hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml . Plasma concentrations of carbamazepine and its epoxide metabolite reached steady state at 1-2 weeks after last dose change. CONCLUSIONSCarbamazepine treatment of paediatric patients with epilepsy resulted in an induction of CYP3A4/5 and a concomitant increase in plasma 4b-hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1-2 weeks, the increase in 4b-hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4b-hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.

Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

“…There were significantly lower 4b-hydroxycholesterol levels in men than in women (P , 0.05). dmd.aspetjournals.org in studies on CYP3A induction (Kanebratt et al, 2008;Wide et al, 2008;Habtewold et al, 2012), showing good concordance with the response in other markers of CYP3A activity such as quinine metabolic ratio (Kanebratt et al, 2008) or the 6b-hydroxycortisol-to-cortisol ratio in urine (Mårde Arrhen et al, 2012). CYP3A4 expression is regulated by a complex network of transcription factors, e.g., the (VDR), pregnane X receptor, and constitutive androstane receptor (Drocourt et al, 2002).…”

Association of Plasma Concentration of 4β-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

“…Among them, 4b-hydroxycholesterol was first reported to be formed solely by CYP3A4 (Bodin et al, 2001). Markedly elevated concentrations of 4b-hydroxycholesterol were found in patients treated with CYP3A4 inducers (Niemi et al, 2006;Josephson et al, 2008;Wide et al, 2008;Diczfalusy et al, 2009;Goodenough et al, 2011), and decreased concentrations have been detected in patients treated with CYP3A4 inhibitors (Josephson et al, 2008;Lütjohann et al, 2009;Goodenough et al, 2011). Furthermore, a relationship between blood 4b-hydroxycholesterol concentration and the number of active CYP3A5*1 alleles has been demonstrated, suggesting that 4b-hydroxycholesterol is not only formed by CYP3A4, but also by CYP3A5 .…”

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

“…8 Its plasma concentration increases in subjects treated with known CYP3A4 inducers such as carbamazepine, phenytoin, phenobarbital, rifampicin, ursodeoxycholic acid and efavirenz. 8,[30][31][32][33][34][35] It was also shown that inhibitors of CYP3A4, ritonavir and itraconazol, reduce the plasma level of 4b-hydroxycholesterol. 35,36 However, recently, TomalikScharte et al 37 reported a weak correlation between cholesterol-and midazolam-based CYP3A metrics and hence questioned the validity of 4b-hydroxycholesterol as a CYP3A biomarker.…”