title: Time course of the increase in 4beta-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Paediatrics, Department of Clinical Sciences, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Wide
authors.forename: Hanna
authors.initials: H
authors.lastname: Larsson
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D007223:Infant; D008297:Male; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human