Fluconazole

Category: pharmacological

Aliases: Diflucan

Pharmacological Mechanism

Triazole antifungal — inhibits Candida / Cryptococcus 14α-demethylase (CYP51) blocking ergosterol synthesis. In humans inhibits CYP2C9, CYP2C19, and CYP3A4 — moderate DDI perpetrator at doses ≥ 200 mg/d (warfarin INR rises predictably). Renally cleared; long t½ allows once-daily dosing.

Half-Life (t½)

PO: 34h, IV: 34h

Dosing Guidelines

PO: Typical 200 mg (Range: 100–400 mg)

Target Organ Systems

digestive
immune-hematologic

Interactions

Warfarin (major): CYP2C9 inhibition. Black 1996 (PMID:8801057): fluconazole 400 mg/d × 6d inhibited S-warfarin 7-hydroxylation by ~70% (AUC ≈ 3.3× increase). Reduce warfarin dose ~50% with fluconazole; monitor INR closely on initiation + discontinuation.
Tacrolimus (major): CYP3A4 inhibition. Lumlertgul 2006 (PMID:17044457): fluconazole reduced tacrolimus CL 38.8→14.7 L/h (62% reduction), allowing dose reduction from 10.7→5.7 mg/d. Kuypers 2008 (PMID:18704002) confirms ~3.3× trough rise in CYP3A5*3/*3 carriers. Empirically halve tacrolimus dose on fluconazole initiation.
Cyclosporine (major): CYP3A4 inhibition. Lopez-Gil 1993 (PMID:8477116): fluconazole 300 mg/d sharply raised cyclosporine trough + serum creatinine in transplant patient; 100 mg/d dose did not. Effect dose-dependent — monitor at fluconazole ≥200 mg/d.
Phenytoin (warn): CYP2C9 inhibition. Touchette 1992 (PMID:1633070) n=9 healthy males, fluconazole 400 mg/d × 6d, single 250 mg phenytoin: AUC0-48 195.2 vs 146.3 µg·h/mL (ratio 1.33×). Ki ≈ 30/0.33 = 89.8 µM. Phenytoin TDM advised — narrow therapeutic index.
Losartan (warn): CYP2C9 inhibition (reduces E-3174 conversion). Kazierad 1997 (PMID:9357393) n=16 males, losartan 100 mg + fluconazole 200 mg/d days 11-20: parent AUC +66%, Cmax +30%; active E-3174 AUC −43%, Cmax −56%. Ki ≈ 30/0.66 = 45.5 µM. Efficacy concern (active metabolite cut), not toxicity.
Ibuprofen (warn): CYP2C9 inhibition. Hynninen 2006 (PMID:16723553) n=12 males, fluconazole 400 mg d1 + 200 mg d2, single 400 mg racemic ibuprofen: S-(+)-AUC ratio 1.82 (90% CI 1.72-1.91). Ki ≈ 30/0.82 = 36.6 µM. Consider dose reduction at high ibuprofen doses.
Celecoxib (warn): CYP2C9 inhibition. Cho 2025 (PMID:39730940) n=39 Korean males by CYP2C9 genotype, fluconazole 150 mg/d + 200 mg celecoxib day 6: in *1/*1 EMs AUCinf increased 2.61×, CL/F −60.4%. Ki ≈ 30/1.61 = 18.6 µM. FDA label: halve celecoxib dose with fluconazole.
Fluvastatin (warn): CYP2C9 inhibition. Kantola 2000 (PMID:10952477) n=12, fluconazole 400 mg d1 + 200 mg/d d2-4, single 40 mg fluvastatin d4: AUC0-∞ +84%, t½ +80%, Cmax +44%. Ki ≈ 30/0.84 = 35.7 µM. Pravastatin unaffected (different transport).
Omeprazole (major): CYP2C19 inhibition (strong). Kang 2002 (PMID:11932962) n=18 males, fluconazole 100 mg/d × 4d then 20 mg omeprazole + 100 mg fluconazole d5: AUC 491→3090 ng·h/mL (6.29×), t½ 0.85→2.59 h, Cmax 311→746 ng/mL. Ki ≈ 30/5.29 = 5.67 µM. >5× AUC = strong CYP2C19 inhibition by FDA criteria.
Diazepam (warn): CYP2C19 inhibition (N-demethylation). Saari 2007 (PMID:17676319) n=12, fluconazole 400 mg d1 + 200 mg d2, single 5 mg PO diazepam: AUC0-∞ 2.5× (90% CI 1.94-3.40), t½ 31→73 h. Ki ≈ 30/1.5 = 20 µM. Sedation prolonged; t½ doubled.
Midazolam (major): CYP3A4 inhibition. Ahonen 1997 (PMID:9049584) n=9 crossover, fluconazole 400 mg PO or IV + oral midazolam 7.5 mg 60 min later: AUC0-3, AUC0-17 increased 2-3×, t½ 2.5×, Cmax 2-2.5×. Ki ≈ 30/1.5 = 20 µM. Oral midazolam route-dependent (more affected than IV).
Triazolam (major): CYP3A4 inhibition. Varhe 1996 (PMID:8904618) n=8, 4-phase crossover, fluconazole 50/100/200 mg/d × 4d + 0.25 mg PO triazolam d4: AUC 1.6×/2.1×/4.4× (P<0.001), dose-dependent. Ki ≈ 30/3.4 = 8.82 µM at 200 mg fluconazole. Label avoidance with high-dose fluconazole.
Glimepiride (caution): CYP2C9 inhibition. Niemi 2001 (PMID:11309547) verbatim: "the mean total area under the plasma concentration-time curve of glimepiride was 238% (P <.0001) ... of the respective control value". 12 healthy volunteers, randomized double-blind 3-phase crossover, fluconazole 400 mg d1 / 200 mg d2-4 + single 0.5 mg PO glimepiride d4. AUC ratio 2.38×; t½ 2.0 → 3.3 h; Ki ≈ 30/1.38 = 21.7 µM. Hypoglycemia risk in diabetics on antifungal therapy.

Pathways It Modulates

Warfarin metabolism (inhibitor) — CYP2C9 (S-warfarin path)

Chemical Identifiers

PubChem CID: 3365
Formula: C13H12F2N6O
Molecular weight: 306.27 g/mol
InChIKey: RFHAOTPXVQNOHP-UHFFFAOYSA-N
SMILES: C1=CC(=C(C=C1F)F)C(CN2C=NC=N2)(CN3C=NC=N3)O