9 popular drugs reduce Vitamin D

Drugs Among the U.S. Top 200 Most-Prescribed That Reduce Vitamin D Delivery to Cells

Claude AI - deep research, June 2026

Summary Table

(qualifying / relevant drugs in ClinCalc Top 200 of 2023)

Rank / # patients (2023)	Drug	Target / mechanism	Reduction amount
#38 — 9.1M patients	Prednisone	↑CYP24A1 (24-hydroxylase) catabolism; ↑VDR/CYP24A1 transcription; ↓Ca absorption; assoc. ↓serum 25(OH)D	Medium
#135 — 3.3M	Methylprednisolone	Same glucocorticoid mechanism	Medium
#146 — 2.5M	Prednisolone	Same	Medium
#108 — 4.3M	Triamcinolone (mostly topical/injectable)	Same (systemic exposure lower)	Small–medium
#182 — 1.4M	Hydrocortisone	Same (often topical)	Small
#162/#74 budesonide; #26/#61/#118/#139 fluticasone	Inhaled/enteric corticosteroids	Same mechanism but low systemic exposure	Minimal/none demonstrated
#185 — 0.5M	Carbamazepine	CYP3A4 induction → ↑catabolism of 25(OH)D; ↓serum 25(OH)D	Medium
#160 — 0.6M	Valproate	Non–enzyme-inducer; lowers 25(OH)D by less clear mechanism	Small
#71 — 2.0M	Topiramate	Weak CYP3A4 inducer (mainly >200 mg/day)	Small
#59 — 2.0M	Lamotrigine	Non-inducer	Minimal/none
#131 — 1.2M	Hydroxychloroquine	Inhibits CYP27B1 conversion of 25(OH)D→1,25(OH)2D	Medium (lowers 1,25(OH)2D; clearest in granulomatous disease)
#140 — 1.8M	Ketoconazole	Inhibits CYP27B1, CYP24A1, CYP3A4 → ↓1,25(OH)2D	Large (on 1,25(OH)2D); complex
#175 — 2.1M	Fluconazole	Weaker partial CYP27B1 inhibition	Small–medium
#10/#13/#147 — omeprazole/ pantoprazole/ esomeprazole	PPIs	Possible ↓absorption / hypomagnesemia affecting hydroxylases	Small / mixed evidence
#179 — 1.3M	Cyclosporine	Calcineurin inhibitor; alters vitamin D/bone metabolism	Small / uncertain

TL;DR

Of the ClinCalc Top 200 Drugs of 2023, the agents with credible evidence of impairing vitamin D status or activation are the systemic glucocorticoids (prednisone #38, methylprednisolone #135, prednisolone #146, triamcinolone #108, hydrocortisone #182), carbamazepine (#185), hydroxychloroquine (#131), ketoconazole (#140) and other azoles (fluconazole #175), and to a weaker/uncertain degree valproate (#160), topiramate (#71), and PPIs (omeprazole #10, pantoprazole #13, esomeprazole #147).
Importantly, the drugs with the strongest, best-quantified evidence in the literature — rifampin, efavirenz, phenytoin, phenobarbital, orlistat, and bile-acid sequestrants — are NOT in the current top 200, so the highest-magnitude classic offenders are largely absent from the most-prescribed list.
Several heavily prescribed drugs commonly assumed to lower vitamin D actually raise total 25(OH)D or are neutral: statins (atorvastatin #1, rosuvastatin #12) trend neutral-to-higher; estrogens/oral contraceptives raise total 25(OH)D ~20% via vitamin D binding protein (free unchanged); thiazides raise serum calcium and modestly lower 1,25(OH)2D but do not lower 25(OH)D; metformin (#2) has no effect.

Key Findings

The user's mechanisms (serum 25(OH)D/1,25(OH)2D reduction; CYP27B1, CYP3A4, CYP24A1, DBP/GC, VDR) map onto the top-200 universe as follows. The single most important framing point: the canonical, large-magnitude vitamin-D-depleting drugs are not on the current most-prescribed list. The drugs that ARE on the list mostly have medium-to-small or mechanism-only effects.

Drugs that RAISE or do NOT lower vitamin D (honest direction correction)

Rank	Drug	Effect / direction
#1, #12, #22, #57, #132	Atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin	Neutral to increase 25(OH)D
#56, #79, #97, #138, #154, #170, #117	Estradiol, ethinyl-estradiol contraceptive combos, progesterone	Increase total 25(OH)D and DBP (~20%); free 25(OH)D unchanged
#16, #124	Hydrochlorothiazide, chlorthalidone	Raise serum calcium, modestly lower 1,25(OH)2D; do not lower 25(OH)D
#2	Metformin	No effect on 25(OH)D (lowers B12)
#29	Furosemide	Increases urinary calcium; no clear 25(OH)D effect

Details by mechanism / class

1. Glucocorticoids (strongest in-list signal; medium magnitude) — CYP24A1 induction + VDR modulation

Systemic glucocorticoids are the most-prescribed in-list drugs with a credible vitamin D mechanism. Prednisone is #38 (≈9.1 million patients in 2023), with methylprednisolone (#135), prednisolone (#146), triamcinolone (#108), and hydrocortisone (#182) also present.

Mechanism (strong, but mostly animal/cell): Glucocorticoids induce CYP24A1 (24-hydroxylase), the catabolic enzyme that inactivates both 25(OH)D and 1,25(OH)2D. In vivo, dexamethasone (2 mg/kg/day) increased renal 24-hydroxylase mRNA up to 16-fold and enzyme activity 9-fold in mouse kidney while decreasing 1α-hydroxylase mRNA (52%) and activity (34%) (Akeno et al., J Endocrinol 2000;164:339–348). Dhawan & Christakos (J Cell Biochem 2010;110:1314–1323) showed a glucocorticoid-receptor–dependent transcriptional mechanism, with GR cooperating with C/EBPβ and VDR to enhance 24-hydroxylase transcription. Separately, dexamethasone increases VDR expression and VDR-mediated transcription (Hidalgo et al.), which is why glucocorticoids are sometimes used to sensitize tumor cells to calcitriol. Notably, Akeno's authors cautioned that glucocorticoid-induced osteoporosis is likely driven more by direct effects on bone than by this renal vitamin D handling.

Human serum evidence (observational; medium): The largest study is Skversky et al. (J Clin Endocrinol Metab 2011;96(12):3838–3845), NHANES 2001–2006, n=22,650. Oral steroid users had 25(OH)D deficiency (<10 ng/mL) prevalence of 11% vs 5% in non-users (P=0.009); the odds ratio for deficiency was 2.36 (95% CI 1.25–4.45) unadjusted and 2.21 (95% CI 1.01–4.85) after multivariable adjustment, and steroid users under 18 were roughly 14 times more likely to be severely deficient. What this does NOT show: the study reports a dichotomous deficiency odds ratio, not a mean ng/mL decrement; and an older controlled comparison (Zerwekh et al.) found virtually identical 25(OH)D in chronic prednisone users vs controls. So the serum-25(OH)D–lowering effect of oral steroids is real epidemiologically but modest and somewhat inconsistent; the cleaner mechanistic effect is accelerated catabolism of 1,25(OH)2D and reduced calcium absorption.

Inhaled/topical corticosteroids (fluticasone, budesonide, triamcinolone, hydrocortisone, clobetasol): Evidence of a serum 25(OH)D effect is weak to absent. A direct test (Columbo et al.) found inhaled steroid dose was not associated with serum vitamin D (r=−0.2, p=0.31). These should be flagged as mechanism-plausible but not demonstrated, given low systemic exposure.

2. Enzyme-inducing / antiseizure medications — CYP3A4 (and CYP24A1) induction

The classic offenders here (phenytoin, phenobarbital, primidone, oxcarbazepine) are not in the top 200. Of the AEDs that ARE:

Carbamazepine (#185): Medium effect, best-quantified AED in-list. A meta-analysis of 12 studies (LoPinto-Khoury, Brennan & Mintzer, PMID 34847425, Epub 2021) found carbamazepine users averaged 21.8 ng/mL 25(OH)D (IQR 15.4–26.0) vs 28.0 ng/mL controls (IQR 20.8–30.4) — a weighted mean difference of 4.00 ng/mL. A pediatric prospective study showed a 21.7% decline (14.45→11.31 ng/mL) over 6 months. Mechanism: CYP3A4 induction accelerating 25(OH)D catabolism to inactive 4β,25(OH)2D (Wang/Thummel work showing rifampin, carbamazepine, and phenobarbital induce CYP3A4 and 25(OH)D 4-hydroxylation).
Valproate (#160): Non–enzyme-inducer, yet meta-analysis shows a small but consistent decline in children (standardized mean difference −0.31); mechanism unclear (possibly enzyme inhibition plus direct bone effects). Small magnitude.
Topiramate (#71): Weak CYP3A4 inducer, clinically relevant mainly at >200 mg/day. Small.
Lamotrigine (#59): Non-inducer; generally no meaningful 25(OH)D effect — often used as the "bone-sparing" comparator. Minimal/none.

3. Azole antifungals — CYP27B1 / CYP24A1 / CYP3A4 inhibition (effect on 1,25(OH)2D)

Ketoconazole (#140): Large but complex. Oral ketoconazole (800 mg/day) reduced serum 1,25(OH)2D by ~40–73% within days in sarcoidosis patients (Glass et al. 1990; Adams et al., JCEM 1990), via inhibition of CYP27B1 (1α-hydroxylase). It also inhibits CYP24A1 and CYP3A4 — so the net effect is reduced activation (lower 1,25(OH)2D) rather than lower 25(OH)D. Note most current ketoconazole prescriptions (#140) are topical, limiting systemic relevance.
Fluconazole (#175): Weaker, partial CYP27B1 inhibition; small–medium and less documented.

4. Hydroxychloroquine (#131) — CYP27B1 inhibition (lowers 1,25(OH)2D)

Hydroxychloroquine inhibits the conversion of 25(OH)D to 1,25(OH)2D (1α-hydroxylase/CYP27B1 pathway). The evidence is clearest in granulomatous disease (sarcoidosis): HCQ and chloroquine normalize elevated 1,25(OH)2D and serum calcium over weeks (Barré et al., Am J Med 1987; O'Leary et al., NEJM 1986; Adams, Ann Intern Med 1989). In people with normal vitamin D physiology, the magnitude of any 1,25(OH)2D reduction is less characterized — flag as medium in granulomatous disease, uncertain in the general population.

5. Acid suppression — PPIs and H2 blockers

PPIs (omeprazole #10, pantoprazole #13, esomeprazole #147): Mixed/weak evidence. Some studies show impaired repletion (one cohort: the "no PPI" group's 25(OH)D improvement was ~64% greater) and a 2023 study found vitamin D deficiency in 100% of long-term pantoprazole users vs controls; other ≥6-month studies found no difference. Proposed mechanism is hypomagnesemia (Mg is a cofactor for 25- and 1α-hydroxylase) and altered absorption. Small/uncertain.
Famotidine (#33): H2 blocker; minimal evidence of a clinically meaningful effect.

6. Immunosuppressants

Cyclosporine (#179): Calcineurin inhibitor associated with bone loss and altered vitamin D/calcium handling; direct serum 25(OH)D effect uncertain/small. (Tacrolimus is not in the top 200.)
Methotrexate (#130): No strong, consistent direct vitamin D pathway effect established.

7. Drugs that RAISE vitamin D or are neutral (direction correction)

Statins (atorvastatin #1, rosuvastatin #12, simvastatin #22, pravastatin #57, lovastatin #132): Evidence indicates neutral-to-increased 25(OH)D, NOT a decrease. Mechanistically statins block conversion of 7-dehydrocholesterol to cholesterol, potentially diverting substrate to vitamin D, and may occupy CYP3A4. In a prospective study of 91 hyperlipidemic patients, rosuvastatin raised 25(OH)D from a mean of 14.0 to 36.3 ng/mL over 8 weeks (Yavuz et al., Cardiovasc Drugs Ther 2009); the randomized STATIN-D trial (Ertugrul et al., Cardiovasc Ther 2011) confirmed rosuvastatin raised 25(OH)D from 11.8 to 35.2 ng/mL while fluvastatin showed no significant change. Atorvastatin raised 25(OH)D modestly (16.4→18.8 ng/mL over 12 months); NHANES showed statin users had ~3–4 nmol/L higher 25(OH)D. Some RCTs (simvastatin) show no change. No evidence statins cause deficiency.
Estrogens / oral contraceptives (estradiol #56; ethinyl-estradiol combos #79, #97, #138, #154, #170; progesterone #117): RAISE total 25(OH)D, 1,25(OH)2D, and DBP via estrogen-induced hepatic DBP synthesis. Harmon et al. (JCEM 2016;101(9):3370) found estrogen-containing contraception was associated with a ~20% increase in serum total 25(OH)D after adjustment; Møller et al. (JCEM 2018;103(6):2385) confirmed users had significantly higher total but a lower percentage of free 25(OH)D. Free/bioavailable 25(OH)D is essentially unchanged — so this is largely an assay artifact of total measurement, not a true status improvement. Important caveat for interpretation.
Thiazides (hydrochlorothiazide #16, chlorthalidone #124): Reduce urinary calcium and can cause mild hypercalcemia with vitamin D/calcium; long-term thiazide modestly lowers serum 1,25(OH)2D (e.g., 5.2→3.7 ng/dL in hypercalciuria) but does NOT lower 25(OH)D. Net effect on calcium is positive.
Metformin (#2): No significant effect on 25(OH)D (lowers B12). Multiple studies including an RCT post-hoc analysis confirm no 25(OH)D change.

8. Notable: highest-magnitude offenders are NOT in the top 200

For completeness and honesty, the drugs with the strongest, best-quantified vitamin-D-lowering evidence are absent from the current top 200: - Rifampin: potent CYP3A4/PXR inducer; lowers 25(OH)D and 1,25(OH)2D; used therapeutically to lower 1,25(OH)2D in CYP24A1-deficient hypercalcemia (Hawkes et al., JCEM 2017). - Efavirenz: induces CYP24A1/CYP3A4. In the ECHO Phase III trial (Wohl et al., Antivir Ther 2014;19:191–200, n=690), efavirenz reduced mean 25(OH)D by ~2.5 ng/mL (vs −0.2 ng/mL for rilpivirine) and roughly doubled the rate of progression to severe deficiency (9% vs 5% at week 48; P=0.032); earlier cohort work reported up to ~98% increased odds of low 25(OH)D — not in top 200. - Phenytoin, phenobarbital, primidone, oxcarbazepine: classic enzyme-inducing AEDs (large effect) — not in top 200. - Orlistat: reduces fat-soluble vitamin D absorption (significant 25(OH)D reduction after 1 month even with multivitamin; ~30% fat-absorption inhibition) — not in top 200. - Bile acid sequestrants (cholestyramine, colesevelam, colestipol): reduce vitamin D absorption — not in top 200. - Isoniazid: affects vitamin D metabolism — not in top 200.

Recommendations

Stage 1 — Highest-yield monitoring among top-200 patients. Prioritize 25(OH)D screening and repletion in patients on chronic systemic glucocorticoids (prednisone/methylprednisolone/prednisolone) and carbamazepine, the two in-list classes with both mechanism and human serum data. Threshold to act: target 25(OH)D ≥30 ng/mL; for carbamazepine expect to need higher supplemental doses (enzyme-inducing AED users require larger doses to reach the same level).

Stage 2 — Active-metabolite awareness. For hydroxychloroquine, ketoconazole (systemic/oral), and fluconazole, recognize the effect is on activation (lower 1,25(OH)2D) rather than 25(OH)D — standard 25(OH)D testing may miss it. Consider measuring 1,25(OH)2D if clinically relevant (e.g., granulomatous disease, unexplained hypocalcemia). Most ketoconazole and triamcinolone/hydrocortisone scripts are topical — verify route before attributing a systemic effect.

Stage 3 — Reassure / do not over-attribute. Do not flag statins, estrogens/contraceptives, thiazides, or metformin as vitamin-D–lowering. For estrogen/contraceptive users, interpret an elevated total 25(OH)D cautiously (DBP-driven; free is unchanged).

Stage 4 — Weak/uncertain signals to watch, not act on yet. PPIs, valproate, topiramate, cyclosporine: monitor opportunistically in patients already at risk (elderly, polypharmacy, malabsorption), but evidence does not justify routine intervention based on these drugs alone.

Benchmarks that would change these recommendations: a well-powered RCT showing a clinically meaningful (>5 ng/mL) 25(OH)D drop attributable to PPIs or inhaled steroids would elevate them to Stage 1; conversely, replication of null oral-prednisone serum data would downgrade glucocorticoids to "monitor only."

Caveats

Evidence tiering: Carbamazepine (meta-analysis of observational + monotherapy studies) and glucocorticoids (NHANES + animal/cell mechanism) are the best-supported in-list. Ketoconazole/HCQ effects on 1,25(OH)2D rest largely on small studies in granulomatous-disease patients, which may not generalize to people with normal vitamin D physiology. PPI, valproate, topiramate, and cyclosporine effects are observational, small, and/or conflicting.
Mechanistic vs serum-demonstrated: CYP24A1 induction by glucocorticoids is robust in animals/cells but the human serum 25(OH)D decrement is modest and inconsistent (Skversky positive; Zerwekh null). Most azole/HCQ data demonstrate 1,25(OH)2D changes, not 25(OH)D.
Route of administration matters: Several "qualifying" entries (triamcinolone, hydrocortisone, clobetasol, ketoconazole, much fluticasone/budesonide) are predominantly topical/inhaled with limited systemic vitamin D impact.
Ranking source: All ranks are from the ClinCalc DrugStats "Top 200 Drugs of 2023" (Kane SP, version 2025.08; source MEPS 2014–2023, AHRQ). ClinCalc aggregates by generic, so combination products (e.g., fluticasone combos, estrogen combos) appear separately, somewhat dispersing class totals.
The biggest takeaway: The drugs most likely to genuinely impair vitamin D delivery to cells (rifampin, efavirenz, phenytoin, phenobarbital, orlistat, bile-acid sequestrants) are NOT among the most-prescribed 200, so population-level drug-induced vitamin D depletion from the top 200 is driven mainly by the very widely used but only medium-magnitude glucocorticoids.

Question asked

:Which of the top 200 most prescribed drugs in the US decrease the amount of vitamin D that gets to the cells? This would include drugs that decrease vitamin D in the blood AND drugs that change the activation of genes that regulate Vitamin D in blood getting into cells: such as CYP27B1, CYP3A4, CPY24A1, Vitamin D Binding, and VDR. Please present the results as a table: Popularity or # of users, Drug name, Drug target, Reduction amount ( large/medium/small?). Details can be explained below the table.

6 drugs that greatly decrease Vitamin D levels are not used much

1. Rifampin — potent CYP3A4/PXR inducer; lowers both 25(OH)D and 1,25(OH)2D by accelerating catabolism. The effect is strong enough that it's used therapeutically to bring down 1,25(OH)2D in CYP24A1-deficiency hypercalcemia.

2. Efavirenz — induces CYP24A1/CYP3A4. In the ECHO Phase III trial (n=690), it reduced mean 25(OH)D ~2.5 ng/mL and roughly doubled progression to severe deficiency vs. rilpivirine; cohort data showed up to ~98% increased odds of low 25(OH)D.

3. Phenytoin — classic enzyme-inducing antiepileptic; large-magnitude depleter via CYP3A4 induction and accelerated 25(OH)D catabolism. A foundational drug in the drug-induced osteomalacia literature.

4. Phenobarbital (and the closely related primidone, which metabolizes to phenobarbital) — same enzyme-inducing AED mechanism; among the original drugs linked to anticonvulsant osteomalacia.

5. Orlistat — lipase inhibitor that blocks fat absorption and therefore fat-soluble vitamin D uptake; produces measurable 25(OH)D reduction even with multivitamin co-administration. Different mechanism (absorption, not catabolism).

6. Bile-acid sequestrants (cholestyramine, colesevelam, colestipol) — bind bile acids and impair absorption of fat-soluble vitamins including D. Also an absorption mechanism.

A couple of close cousins worth noting in the same tier even though I listed them separately: oxcarbazepine (enzyme-inducing AED, like phenytoin/phenobarbital) and isoniazid (affects vitamin D hydroxylation).