CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations.
The P450 enzyme CYP24A1 is the principal inactivator of vitamin D metabolites. Biallelic loss-of-function mutations in CYP24A1 are associated with elevated serum levels of 1,25-dihydroxyvitamin D3 with consequent hypercalcemia and hypercalciuria and represent the most common form of idiopathic infantile hypercalcemia (IIH). Current management strategies for this condition include a low-calcium diet, reduced dietary vitamin D intake, and limited sunlight exposure. CYP3A4 is a P450 enzyme that inactivates many drugs and xenobiotics and may represent an alternative pathway for inactivation of vitamin D metabolites.



Our goal was to determine if rifampin, a potent inducer of CYP3A4, can normalize mineral metabolism in patients with IIH due to mutations in CYP24A1.



We treated two patients with IIH with daily rifampin (10 mg/kg/d, up to a maximum of 600 mg). Serum calcium, phosphorus, parathyroid hormone (PTH), liver, and adrenal function and vitamin D metabolites, as well as urinary calcium excretion, were monitored during treatment of up to 13 months.



Prior to treatment, both patients had hypercalcemia, hypercalciuria, and nephrocalcinosis with elevated serum 1,25-dihydroxyvitamin D3 and suppressed serum PTH. Daily treatment with rifampin was well tolerated and led to normalization or improvement in all clinical and biochemical parameters.



These observations suggest that rifampin-induced overexpression of CYP3A4 provides an alternative pathway for inactivation of vitamin D metabolites in patients who lack CYP24A1 function.
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.|National Children's Research Centre, Crumlin, Dublin, D12 V004, Ireland.
Colin Patrick
CP
Hawkes
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Dong
D
Li
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Hakon
H
Hakonarson
Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Kevin E
KE
Meyers
Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, Washington 98155.
Kenneth E
KE
Thummel
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Michael A
MA
Levine
D000293:Adolescent; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood / Q000652:urine; D002648:Child; D065701:Cytochrome P-450 CYP3A Inducers / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D053565:Hypercalciuria / Q000209:etiology; D007232:Infant, Newborn, Diseases / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D009397:Nephrocalcinosis / Q000209:etiology; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D012293:Rifampin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014807:Vitamin D / Q000097:blood; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
D065701:Cytochrome P-450 CYP3A Inducers; D010281:Parathyroid Hormone; D014807:Vitamin D; D010758:Phosphorus; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium; D012293:Rifampin