Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment.
Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disorder with cholestanol accumulation resulting from mutations in the sterol 27-hydroxylase gene (CYP27A). Conventional treatment includes chenodeoxycholic acid and HMG-CoA reductase inhibitors. Mice with disrupted Cyp27A (Cyp27 KO) do not show elevated cholestanol levels nor develop CTX manifestations. This phenomenon was proposed to be due to murine CYP3A overexpression leading to an alternative pathway for degradation of bile alcohols including cholestanol. Our objective was to examine the influence of CYP3A4 induction on cholestanol elimination in CTX patients. Rifampicin (600 mg/day x 7 days), known to induce the PXR, and thereby to increase CYP3A activity, was used. The degree of CYP3A4 induction was assessed by comparing midazolam pharmacokinetics before and after rifampicin treatment. Cholestanol levels and cholestanol/cholesterol ratios were assayed during the experimental period and compared to a 3 weeks period without treatment. The results show that despite 60% increase in CYP3A4 activity following rifampicin treatment, there is no significant change in cholestanol levels. We conclude that up-regulated expression of CYP3A affects cholestanol elimination in mice differently as compared to its effect in CTX patients. Therefore, CYP3A4 inducers cannot replace chenodeoxycholic acid for the treatment of CTX.
Szalat
Auryan
A
Department of Internal Medicine B and the Center for Research Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Gershkovich
Pavel
P
Ben-Ari
Alon
A
Shaish
Aviv
A
Liberman
Yael
Y
Boutboul
Eti
E
Gotkine
Marc
M
Hoffman
Amnon
A
Harats
Dror
D
Leitersdorf
Eran
E
Meiner
Vardiella
V
D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000627:therapeutic use*; D004083:Cholestanol / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D018757:GABA Modulators / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*; D019294:Xanthomatosis, Cerebrotendinous / Q000188:drug therapy* / Q000201:enzymology*
D000904:Antibiotics, Antitubercular; D001647:Bile Acids and Salts; D018757:GABA Modulators; D002635:Chenodeoxycholic Acid; D004083:Cholestanol; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D012293:Rifampin