CYP3A4 Induction by Rifampin: an Alternative Pathway for Vitamin D Inactivation in Patients with CYP24A1 Mutations

CASE REPORT

CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations

Colin Patrick Hawkes,1,2 Dong Li,3 Hakon Hakonarson,3 Kevin E. Meyers,4,5 Kenneth E. Thummel,6 and Michael A. Levine1,5 Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021

1Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; 2National Children’s Research Centre, Crumlin, Dublin, D12 V004, Ireland; 3Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; 4Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; 5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and 6Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, Washington 98155

Context: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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. (J Clin Endocrinol Metab 102: 1440–1446, 2017)

diopathic infantile hypercalcemia (IIH) (OMIM hormone (PTH), and elevated levels of vitamin D me- I 143880) is an uncommon disorder of vitamin D tabolites, particularly the active form of vitamin D, 1,25- metabolism that is characterized by hypersensitivity to dihydroxyvitamin D. Biallelic loss-of-function mutations vitamin D. It is associated with hypercalcemia and of CYP24A1, the gene encoding a P450 24-hydroxylase hypercalciuria, suppressed serum levels of parathyroid enzyme that represents the principal pathway for

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: IIH, idiopathic infantile hypercalcemia; PTH, parathyroid hormone. Printed in USA Copyright © 2017 Endocrine Society Received 29 December 2016. Accepted 28 February 2017. First Published Online 3 March 2017

1440 https://academic.oup.com/jcem J Clin Endocrinol Metab, May 2017, 102(5):1440–1446 doi: 10.1210/jc.2016-4048 doi: 10.1210/jc.2016-4048 https://academic.oup.com/jcem 1441

inactivation of vitamin D metabolites (Fig. 1), cause the of 1,25-dihydroxyvitamin D3, which provides further most common and severe form of IIH (1, 2). support for such a therapeutic strategy (9). Here we describe Although IIH is usually diagnosed in infants who the use of rifampin, a potent inducer of CYP3A4 (8), to present with severe hypercalcemia, failure to thrive, and normalize mineral metabolism in two patients with IIH due nephrocalcinosis (3, 4), inactivating mutations of CYP24A1 to mutations in CYP24A1. have also been reported in adults with nephrocalcinosis and/or recurrent nephrolithiasis associated with hyper- Patients and Methods calciuria (5). Patients with CYP24A1 mutations have a life- long defect in vitamin D metabolism that increases risk for Clinical nephrocalcinosis, nephrolithiasis, and renal insufficiency. Two patients with CYP24A1 mutations, hypercalcemia, Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021 There is no specific, long-term treatment for patients and/or hypercalciuria initiated treatment with rifampin as compassionate rescue therapy. Both patients consented or with vitamin D hypersensitivity due to CYP24A1 mu- assented to the off-label use of rifampin. Rifampin dosages in tations, and conventional management consists of min- these patients were consistent with standard antituberculous imizing cutaneous vitamin D production through reduced treatment (10 mg/kg, up to a maximum of 600 mg daily), at exposure to sunlight and other sources of ultraviolet B which rifampin has a very low risk of hepatotoxicity (10) or radiation, a low-calcium diet, and avoidance of vitamin increased catabolism of adrenal hormones (11). Liver and – adrenal function were monitored throughout treatment. In D rich foods and supplements. These restrictions can addition to routine clinical studies, biochemical and mo- reduce serum calcium levels to near normal but do not lecular studies were performed under a protocol that was adequately address the risk of renal complications due to approved by the Institutional Review Board of The Chil- persistent hypercalciuria. Hence, the need for specific dren’s Hospital of Philadelphia. Chart review was per- treatment has stimulated interest in pharmacological formed in accordance with the policies and procedures of the Institutional Review Board as a retrospective review of a approaches to modify vitamin D metabolism. limited case series. Recent reports have demonstrated short-term benefits of treatment with ketoconazole (6) and fluconazole (7), Molecular analyses imidazole derivatives that can partially inhibit CYP27B1, Genomic DNA was isolated from peripheral blood mono- the enzyme that generates 1,25-dihydroxyvitamin nuclear cells of the patients and their first-degree relatives.

D3 from substrate 25-hydroxyvitamin D3. Induction of CYP24A1 mutations were confirmed by Sanger sequencing CYP3A4 (EC 1.14.13.97), an enzyme that is expressed in after the variants were initially identified by whole-exome se- quence analysis of the two probands (12). the liver, small intestine, and other tissues and that me- tabolizes many xenobiotics, steroids, and drugs, repre- Biochemical analyses sents an alternative therapeutic strategy to reduce serum We measured urine and serum calcium, phosphorus, creati- levels of vitamin D metabolites. Indeed, the phenomenon nine, and alkaline phosphatase by standard methods. Measure- of drug-induced vitamin D deficiency and osteomalacia is a ments of vitamin D3 and vitamin D metabolites were performed well-recognized complication of many medications that by liquid chromatography tandem mass spectrometry, with an induceCYP3A4(8)andestablishesCYP3A4asanalter- ultrahigh-resolution chromatographic separation procedure (13) used to enable complete separation of 1,25-dihydroxyvitamin native degradative pathway to CYP24A1 (Fig. 1). Our D3 from 4b,25-dihydroxyvitamin D3, the principal product of group recently identified a recurrent gain-of-function mu- CYP3A4 oxidation of 25-hydroxyvitamin D3 (8). Thus, we used tation in CYP3A4 that results in enhanced bioinactivation the serum concentration of 4b,25-dihydroxyvitamin D3 and the ratio of 4b,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 as biomarkers of CYP3A4 activity. Intact PTH was measured using the Immulite 2000 PTH assay (Diagnostics Product Corp., Los Angeles, CA). Reference ranges of vitamin D metabolites were determined in a subset of 23 healthy young subjects living in Seattle, WA, as described elsewhere (8).

Results

Patients Case 1 Figure 1. The activation and inactivation pathways of vitamin D, demonstrating the role of CYP24A1 in inactivating 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25 An 18-year-old man presented (OH)2D] and the potential of CYP3A4 to provide an alternative inactivation pathway. with unexplained hypercalcemia, 1442 Hawkes et al Rifampin Treatment in CYP24A1 Hypercalcemia J Clin Endocrinol Metab, May 2017, 102(5):1440–1446 hypercalciuria, and recurrent episodes of hematuria. Se- Case 2 rum levels of PTH were suppressed; analyses of serum An 8-year-old girl presented 2 years previously with concentrations of vitamin D metabolites revealed low poor growth, hypercalcemia (albumin-adjusted calcium or undetectable levels of 24,25-dihydroxyvitamin D, concentration of 12.8 mg/dL), and hypercalciuria (uri- elevated or inappropriately normal concentrations of nary calcium/creatinine ratio of 0.59 mG/mG; nor-

1,25-dihydroxyvitamin D3, and an elevated level of mal ,0.22 mG/mG). Serum PTH was suppressed at 25-hydroxyvitamin D, likely the result of extensive 4 pg/mL, and serum 1,25-dihydroxyvitamin D3 was sunbathing without use of an ultraviolet B–blocking inappropriately normal at 49 pg/mL. She had been sunscreen and unrestrained consumption of vitamin treated with intravenous pamidronate and was receiving D–fortified milk prior to elucidation of his genetic subcutaneous calcitonin, as well as a low-calcium and Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021 diagnosis (Table 1). low–vitamin D diet, immediately before beginning The proband carries two CYP24A1 mutations, a novel rifampin (Table 1). maternal deletion (c.1421delT; p.L474WfsX102) that is Case 2 was compound heterozygous for two previously predicted to be pathogenic and a previously reported paternal reported CYP24A1 mutations, a three–base pair deletion missense mutation (c.443T.C; p.L148P) (5) that reduces in exon 2 (c.428_430delAAG:p.Glu143del) inherited from CYP24A1 activity by 30% to 50% (14). Ultrasonography her mother and a paternal missense mutation (c.1186C.T: revealed extensive bilateral nephrocalcinosis and p.R396W) that encodes a CYP24A1 enzyme with no ac- multiple renal parenchymal cysts (maximum size, tivity (2). Her older brother and sister are heterozygous for 2cm3 2.9 cm); the patient had reduced renal function the paternal mutation, and a second sister is wild type for with a serum creatinine concentration of 1.4 mg/dL. both CYP24A1 alleles. All heterozygous carriers were Within 1 month of treatment with 600 mg rifampin clinically and biochemically unaffected. daily, there was marked improvement in mineral meta- Case 2 was treated with rifampin (300 mg daily). Serum bolism, with reductions in serum levels of 1,25-dihy- levels of albumin-adjusted calcium declined from 10.7 to droxyvitamin D3 and calcium and increasing PTH into 9.8 mg/dL, with a corresponding increase in previously the normal range (Table 1; Fig. 2). Urinary calcium ex- suppressed intact PTH concentration from 3 to 31 pg/mL cretion declined, and the serum creatinine improved to (Table 1; Fig. 2). Her polyuria resolved, and her linear 1.1 mg/dL. Both heterozygous parents were clinically growth improved. One month after discontinuation of unaffected. rifampin, her serum and urinary calcium levels increased,

Table 1. Baseline Characteristics of Both Patients and Response to Treatment

Reference Range Case 1 Case 2 Sex, age Male, 18 y Female, 8 y Weight 68.3 kg 22.5 kg Presentation Hematuria, nephrocalcinosis Polyuria, nephrocalcinosis, hypercalcemia Rifampin dose 600 mg daily 300 mg daily Baseline 1 mo 10 mo Baseline 11 mo 13 mo (off (on treatment) treatment 3 2mo) Albumin adjusted calcium, mg/dL 8.9–10.4 10.5 9.6 9.6 10.7 10 11.5 Phosphorus, mg/dL 2.5–4.5 3.6 3.1 4.1 4.2 3.6 4.5 Alkaline phosphatase, U/L 184–415 (Case 1) 82 114 84 242 467 345 0.2–0.73 (Case 2) Intact PTH, pg/mL 9–69 2 13 16 3 31 3 Creatinine, mg/dL 0.3–0.8 (Case 1) 1.4 1.2 1.1 0.59 0.54 0.65 0.2–0.73 (Case 2) 25(OH)D3, ng/mL 28 6 27 102 83 65 23 16 35 1,25-dihydroxyvitamin D3, pg/mL 56 6 27 99 53 59 55 58 76 a 24,25-dihydroxyvitamin D3, ng/mL 1.6 6 1 Undetectable 0.2 0.1 Undetectable 0.1 0.1 25-hydroxyvitamin D3/24,25- 22 6 13 N/Ab 415 650 N/A 160 350 dihydroxyvitamin D3, ng/ng c 4b,25-dihydroxyvitamin D3, pg/mL 53 6 34 275 594 528 N/A 82 56.7 4b,25-dihydroxyvitamin 2.1 6 0$7 2.7 7.2 5.4 N/A 3.7 1.3 23 c D3/25-hydroxyvitamin D3,(10 ) aTest was performed, but the concentration was below the detectable limits of the assay. bNot tested. c 4b,25-dihydroxyvitamin D3 and the 4b,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 ratio are biomarkers of CYP3A4 induction. doi: 10.1210/jc.2016-4048 https://academic.oup.com/jcem 1443 Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021

Figure 2. Serum calcium, PTH, 1,25-dihydroxyvitamin D3 [1,25(OH)2D], and urinary calcium/creatinine concentrations before and during rifampin treatment in Case 1 and Case 2. Note that Case 2 had been treated with pamidronate, calcitonin, low-calcium diet, and reduced vitamin D intake prior to starting rifampin treatment. Case 2 also had a period of observation after discontinuation of rifampin treatment after month 11, with rebound hypercalcemia and suppression of PTH.

her 1,25-dihydroxyvitamin D3 concentration rose from 58 hypercalciuria through the inactivation of 25- to 90 pg/mL, and the serum concentration of intact PTH hydroxyvitamin D and 1,25-dihydroxyvitamin D. Both was once again suppressed (Fig. 2). patients described in this report had biallelic loss-of- Both patients had very low or undetectable serum levels function mutations in CYP24A1; nevertheless, both pa- of 24,25-dihydroxyvitamin D and extremely high ratios tients had detectable circulating 24,25-dihydroxyvitamin of 25-hydroxyvitamin D/24,25-dihydroxyvitamin D, which may be due to residual CYP24A1 activity or D, consistent with an absence of CYP24A1 activity modest 24-hydroxylase activity of other P450 enzymes.

(Table 1). The ratio of serum 4b,25-dihydroxyvitamin D3, Here we have demonstrated that rifampin is a potential an inactive metabolite of 25-hydroxyvitamin D generated treatment of this condition. The likely mechanism of action by CYP3A4 (13, 15), to substrate 25-hydroxyvitamin D is through overexpression of CYP3A4, thereby providing is a marker of CYP3A4 activity and induction (8), and an alternative enzymatic pathway for inactivating vitamin ratios remained elevated in both cases during rifampin D metabolites in patients with CYP24A1 mutations. treatment. Moreover, this ratio decreased in case 2 after With rifampin treatment, both patients described in this discontinuation of rifampin (Table 1). Both patients tol- study experienced biochemical and clinical improvement, erated rifampin without developing hepatic dysfunction, with normalization of serum and urine concentrations of adrenal insufficiency, or symptoms that could be attrib- calcium and relief of symptoms of hypercalcemia. In addition, uted to side effects of therapy. serum concentrations of intact PTH increased to the normal range, signaling re-establishment of normal mineral homeo- Discussion stasis. CYP3A4 oxidizes 1,25-dihydroxyvitamin D and 25- hydroxyvitamin D (Fig. 1) to theinactivemetabolites Normal vitamin D homeostasis requires biochemical 1,23,25-trihydroxyvitamin D and 4b,25-dihydroxyvitamin equipoise between production and inactivation of D, respectively. Although serum levels of 1,23,25 1,25-dihydroxyvitamin D, with CYP24A1 playing a trihydroxyvitamin D were not measured in this study, we critical role in the defense against hypercalcemia and found significant increases in the serum concentrations of 1444 Hawkes et al Rifampin Treatment in CYP24A1 Hypercalcemia J Clin Endocrinol Metab, May 2017, 102(5):1440–1446

4b,25-dihydroxyvitamin D, which provide evidence for combination with other antituberculous medications, are CYP3A4 induction as the mechanism for this clinical well tolerated (19). Rifampin can increase hydrocortisone improvement. Further proof of the therapeutic effect of metabolism and, when used at higher doses than used here, rifampin was provided by subject 2, who- decided to stop has been reported to cause adrenal crisis in patients with treatment after 11 months and experienced a recurrence underlying adrenal insufficiency (11), but clinically sig- of hypercalcemia and hypercalciuria within 1 month of nificant disturbances in the metabolism of other steroid discontinuation of rifampin. hormones in otherwise healthy patients have not been In both cases, serum concentrations of 25- described. Serum levels of adrenocorticotropic hormone hydroxyvitamin D declined with treatment. In case and cortisol, measured in the morning, remained 2, 1,25-dihydroxyvitamin D concentrations were in- normal in our subjects during the study, indicating that appropriately normal or elevated prior to treatment with rifampin treatment had not critically impaired pro- Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021 rifampin despite hypercalcemia and suppressed serum duction of glucocorticoid steroids. We did not perform PTH. With treatment, the serum concentration of 1,25- adrenocorticotropic hormone stimulation tests, how- dihydroxyvitamin D did not decrease significantly but ever, due to the absence of concerning clinical or was now associated with normal serum levels of calcium biochemical features. Nevertheless, the specific dosage and PTH, indicating that 1,25-dihydroxyvitamin D ho- of rifampin that is necessary to induce CYP3A4 ex- meostasis was now physiological. These observations are pression to optimal therapeutic benefit is unknown. It consistent with the notion that intracellular levels rather is also possible that other related antibiotics would than serum levels of 1,25-dihydroxyvitamin D are the have similar effects in this condition because rifabutin primary determinant of vitamin D action. Accordingly, hasbeenreportedtobeassociatedwithosteomalacia the most significant improvement was a marked re- (20, 21). duction in urinary excretion of calcium, presumably The imidazoles fluconazole and ketoconazole have due to decreased vitamin D–dependent absorption of also been reported as a potential treatment of calcium from the intestine. CYP3A4 is highly expressed in patients with elevated serum concentrations of 1,25- the small intestine and liver (16) and is induced in both of dihydroxyvitamin D, including patients with CYP24A1 these tissues by rifampin (17). Hence, it is possible that the mutations, due to their ability to inhibit CYP27B1 and therapeutic effect of rifampin is less dependent upon in- thereby reduce production of 1,25-dihydroxyvitamin D3 duction of CYP3A4 in the liver than in the enterocytes, (22). Nguyen et al. (6) used ketoconazole at 3–9mg/kg/dto where induction of CYP3A4 would lead to increased treat 10 of 20 infants with IIH, many of whom likely had local degradation of 1,25-dihydroxyvitamin D3,thereby unidentified CYP24A1 mutations, for several months. directly reducing calcium transport across the apical Serum calcium and urinary calcium excretion decreased cell membrane. to normal in treated and untreated children, although The current treatment recommendations for pa- normalization of serum calcium was achieved earlier in tients with IIH due to CYP24A1 mutations consist of treated children. By contrast, the time required to reach limiting sunlight exposure and avoiding dietary vita- the upper normal limit for calcium/creatinine ratio was min D, reflecting the effect of the mutation on both not significantly different in the two groups. Of concern is 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in that one of the nine treated infants developed a marked the pathophysiology of this disease. Hence, an approach reduction in serum cortisol that required cessation of that focuses on restoring vitamin D homeostasis to ketoconazole treatment (6). A similar approach was re- normal, not merely blocking conversion of 25-hydrox- ported as effective by Tebben et al. (23) in a single adult yvitamin D to 1,25-dihydroxyvitamin D, would be de- patient. However, ketoconazole requires administration sirable for optimal therapeutic benefit. In both patients three times daily and has a less favorable side effect reported here, rifampin therapy achieved that goal, but it profile, which can include hepatotoxicity, gastrointestinal is likely that long-term treatment with rifampin will be complaints, adrenal insufficiency, and hypogonadism required to prevent ongoing hypercalcemia and com- (24). Although the incidence of fluconazole-related plications of hypercalciuria. hepatotoxity is lower than that associated with ketoco- Rifampin is among the most powerful inducers of nazole, severe jaundice, fatal acute hepatic necrosis, and CYP3A4 and has an extensive history of protracted use even death have been reported (25). Finally, it is worth for a variety of chronic infections with an excellent noting that both fluconazole and ketoconazole can also safety profile. In 157 adolescents treated with rifampin at inhibit CYP3A4 (26), an undesirable effect of treatment. In similar doses to these cases, 2.5% discontinued treatment one other infant with biallelic CYP24A1 mutations that we due to alanine aminotransferase above two times the upper have managed, severe hypercalcemia was induced by limit of normal (18). Short periods of higher doses, even in fluconazole that had been prescribed for an infection. doi: 10.1210/jc.2016-4048 https://academic.oup.com/jcem 1445

Once fluconazole was discontinued, the infant’s serum and 2. Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, urinary calcium levels normalized. Taken together with the Misselwitz J, Klaus G, Kuwertz-Broking ¨ E, Fehrenbach H, Wingen AM, Guran ¨ T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, salutatory effect of rifampin that we show here, it is Konrad M. Mutations in CYP24A1 and idiopathic infantile hy- possible that the reduced penetrance of CYP24A1 muta- percalcemia. N Engl J Med. 2011;365(5):410–421. tions in some affected individuals may reflect the co- 3. Lightwood R, Stapleton T. Idiopathic hypercalcaemia in infants. Lancet. 1953;265(6779):255–256. existence of CYP3A4 alleles that are characterized as “high 4. Creery RD, Neill DW. Idiopathic hypercalcaemia in infants with metabolizing” (27) and that act as important modifiers failure to thrive. Lancet. 1954;267(6829):110–114. that ameliorate the severity of the biochemical defect in 5. Nesterova G, Malicdan MC, Yasuda K, Sakaki T, Vilboux T, vitamin D homeostasis. Ciccone C, Horst R, Huang Y, Golas G, Introne W, Huizing M, Adams D, Boerkoel CF, Collins MT, Gahl WA. 1,25-(OH)2D-24 The effects of loss-of-function CYP24A1 mutations hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis. Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021 remain challenging to treat, with ongoing risk of hy- Clin J Am Soc Nephrol. 2013;8(4):649–657. percalcemia, hypercalciuria, and nephrocalcinosis. The 6. Nguyen M, Boutignon H, Mallet E, Linglart A, Guillozo H, Jehan potential for renal damage is significant, as evidenced F, Garabedian M. Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to by the increased serum creatinine in case 1 and the ketoconazole treatment. J Pediatr. 2010;157(2):296–302. presence of multiple small renal cysts in both of our 7. Sayers J, Hynes AM, Srivastava S, Dowen F, Quinton R, Datta HK, patients. These renal cysts have previously been re- Sayer JA. Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. Clin Kidney J. 2015;8(4): ported in other patients with CYP24A1 mutations (28) 453–455. and likely reflect blockage of small renal collecting 8. Wang Z, Lin YS, Zheng XE, Senn T, Hashizume T, Scian M, ducts by microcalcification. Our results suggest that Dickmann LJ, Nelson SD, Baillie TA, Hebert MF, Blough D, Davis CL, Thummel KE. An inducible cytochrome P450 3A4-dependent rifampin is an alternative treatment to consider in pa- vitamin D catabolic pathway. Mol Pharmacol. 2012;81(4): tients with recalcitrant hypercalcemia and/or hyper- 498–509. calciuria due to excessive 1,25-dihydroxyvitamin D, 9. Roizen J, Li D, O’Lear L, Javaid MK, Shaw N, Ebeling P, Nguyen but confirmation of this proposal should be explored H, Rodda C, Thummel KE, Hakonarson H, Levine MA. Vitamin D deficiency due to a recurrent gain-of-function mutation in CYP3A4 with further studies. In the meantime, it would seem causes a novel form of vitamin D dependent rickets. Paper prudent to avoid the use of medications (29) and foods presented at: ASBMR Symposium on Bone-omics: Translating (e.g., starfruit, pomegranate, and white grapefruit) Genomic Discoveries into Clinical Applications; September 15, 2016; Atlanta, GA. that can inhibit CYP3A4 in patients with CYP24A1 10. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan mutations. CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An Acknowledgments official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–952. Address all correspondence and requests for reprints to: 11. Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicin- Michael A. Levine, MD, Division of Endocrinology and Di- induced adrenal crisis in addisonian patients receiving corticoste- 59 ’ roid replacement therapy. J Clin Endocrinol Metab. 1984; (6): abetes, The Children s Hospital of Philadelphia, Philadelphia, 1204–1206. Pennsylvania 19104. E-mail: [email protected]. 12. Li D, Tian L, Hou C, Kim CE, Hakonarson H, Levine MA. As- This work was supported in part by Grant R01 DK079970 sociation of mutations in SLC12A1 encoding the NKCC2 from the National Institute of Diabetes and Digestive and cotransporter with neonatal primary hyperparathyroidism. J Clin 101 – Kidney Diseases (to M.A.L.); by Grant R01GM063666 from Endocrinol Metab. 2016; (5):2196 2200. the National Institutes of General Medical Sciences (to K.E.T.); 13. Wang Z, Lin YS, Dickmann LJ, Poulton EJ, Eaton DL, Lampe JW, Shen DD, Davis CL, Shuhart MC, Thummel KE. En- by Grant UL1TR000003 from the National Center for Research hancement of hepatic 4-hydroxylation of 25-hydroxyvitamin Resources and the National Center for Advancing Trans- D3 through CYP3A4 induction in vitro and in vivo: implications lational Sciences, National Institutes of Health; and by a PhD for drug-induced osteomalacia. J Bone Miner Res. 2013;28(5): grant from the National Children’s Research Centre, Dublin, 1101–1116. Ireland (to C.P.H.). The content is solely the responsibility of 14. Kaufmann M, Prosser DE, Jones G. Bioengineering anabolic vitamin D-25-hydroxylase activity into the human vitamin D cata- the authors and does not necessarily represent the official bolic enzyme, cytochrome P450 CYP24A1, by a V391L mutation. views of the NIH. J Biol Chem. 2011;286(33):28729–28737. Disclosure Summary: The authors have nothing to disclose. 15. Wang Z, Senn T, Kalhorn T, Zheng XE, Zheng S, Davis CL, Hebert MF, Lin YS, Thummel KE. Simultaneous measurement of plasma vitamin D(3) metabolites, including 4b,25-dihydroxyvitamin D(3), References using liquid chromatography-tandem mass spectrometry. Anal Biochem. 2011;418(1):126–133. 1. Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, 16. Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T, Carpenter TO, Hirschhorn JN. Genetic defect in CYP24A1, Kalhorn TF, Watkins PB, Schuetz EG, Thummel KE. Intestinal and the vitamin D 24-hydroxylase gene, in a patient with severe hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin infantile hypercalcemia. J Clin Endocrinol Metab. 2012;97(2): D(3): implications for drug-induced osteomalacia. Mol Pharmacol. E268–E274. 2006;69(1):56–65. 1446 Hawkes et al Rifampin Treatment in CYP24A1 Hypercalcemia J Clin Endocrinol Metab, May 2017, 102(5):1440–1446

17. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins dominant transmission due to CYP24A1 mutations: effects of keto- PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in conazole therapy. J Clin Endocrinol Metab. 2012;97(3):E423–E427. human small bowel enterocytes. J Clin Invest. 1992;90(5): 24. Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, 1871–1878. Caron P, Luca F, Donadille B, Vantyghem MC, Bihan H, Delemer 18. Villarino ME, Ridzon R, Weismuller PC, Elcock M, Maxwell RM, B, Raverot G, Motte E, Philippon M, Morange I, Conte-Devolx B, Meador J, Smith PJ, Carson ML, Geiter LJ. Rifampin preventive Quinquis L, Martinie M, Vezzosi D, Le Bras M, Baudry C, Christin- therapy for tuberculosis infection: experience with 157 adolescents. Maitre S, Goichot B, Chanson P, Young J, Chabre O, Tabarin A, Am J Respir Crit Care Med. 1997;155(5):1735–1738. Bertherat J, Brue T. Ketoconazole in Cushing’s disease: is it worth a 19. Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter try? J Clin Endocrinol Metab. 2014;99(5):1623–1630. A, Phillips PP, Gillespie SH, McHugh TD, Hoelscher M, Heinrich 25. Wingard JR, Leather H. Hepatotoxicity associated with antifungal N, Rehal S, van Soolingen D, van Ingen J, Magis-Escurra C, Burger therapy after bone marrow transplantation. Clin Infect Dis. 2005; D, Plemper van Balen G, Aarnoutse RE, Pan AC; PanACEA 41(3):308–310. Consortium. A dose-ranging trial to optimize the dose of rifampin 26. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015; cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities Downloaded from https://academic.oup.com/jcem/article/102/5/1440/3061632 by guest on 28 September 2021 191(9):1058–1065. in human liver microsomes. Biol Pharm Bull. 2005;28(9): 20. Bolland MJ, Grey A, Horne AM, Thomas MG. Osteomalacia in an 1805–1808. HIV-infected man receiving rifabutin, a cytochrome P450 enzyme 27. Zanger UM, Klein K, Richter T, Toscano C, Zukunft J. Impact of inducer: a case report. Ann Clin Microbiol Antimicrob. 2008;7:3. genetic polymorphism in relation to other factors on expression and 21. Pentikis HS, Connolly M, Trapnell CB, Forbes WP, Bettenhausen function of human drug-metabolizing p450s. Toxicol Mech DK. The effect of multiple-dose, oral rifaximin on the pharmaco- Methods. 2005;15(2):121–124. kinetics of intravenous and oral midazolam in healthy volunteers. 28. Gigante M, Santangelo L, Diella S, Caridi G, Argentiero L, Pharmacotherapy. 2007;27(10):1361–1369. D’’Alessandro MM, Martino M, Stea ED, Ardissino G, Carbone V, 22. Breslau NA, Preminger GM, Adams BV, Otey J, Pak CY. Use of Pepe S, Scrutinio D, Maringhini S, Ghiggeri GM, Grandaliano G, ketoconazole to probe the pathogenetic importance of 1,25- Giordano M, Gesualdo L. Mutational spectrum of CYP24A1 gene dihydroxyvitamin D in absorptive hypercalciuria. J Clin Endo- in a cohort of italian patients with idiopathic infantile hypercal- crinol Metab. 1992;75(6):1446–1452. cemia. Nephron. 2016;133(3):193–204. 23. Tebben PJ, Milliner DS, Horst RL, Harris PC, Singh RJ, Wu Y, 29. Zhou SF. Drugs behave as substrates, inhibitors and inducers ForemanJW,ChelminskiPR,KumarR.Hypercalcemia,hyper- of human cytochrome P450 3A4. Curr Drug Metab. 2008;9(4): calciuria, and elevated calcitriol concentrations with autosomal 310–322.