cyp3a4
53 interactions related to cyp3a4
apixaban + st. john's wort
St. John's wort strongly induces both CYP3A4 (apixaban's primary metabolizing enzyme) and P-glycoprotein (its efflux transporter). Co-use accelerates apixaban metabolism and clearance, lowering plasma concentrations and increasing the risk of stroke or thromboembolism.
pravastatin + grapefruit
Unlike simvastatin, lovastatin, and atorvastatin, pravastatin is not significantly metabolized by CYP3A4, so grapefruit juice does not meaningfully change its plasma exposure. Clinical pharmacokinetic studies show no significant effect of grapefruit juice on pravastatin disposition.
carvedilol + st. john's wort
Carvedilol is metabolized by CYP2D6, CYP2C9, CYP3A4, and CYP1A2, and is also a P-glycoprotein substrate. St. John's Wort potently induces several of these enzymes and P-gp, accelerating carvedilol clearance and reducing plasma levels, which can blunt its heart failure and antihypertensive effects.
verapamil + st. john's wort
St. John's wort is a potent inducer of intestinal CYP3A4 and P-glycoprotein. In a controlled study, two weeks of St. John's wort reduced the AUC of R- and S-verapamil by roughly 78-80%, dramatically lowering systemic drug exposure and likely therapeutic effect.
digoxin + st. john's wort
St. John's wort induces intestinal P-glycoprotein, increasing efflux of digoxin and reducing its absorption. Controlled studies show digoxin AUC falls roughly 25% and peak concentrations around 30-36% after two weeks of St. John's wort, potentially producing therapeutic failure in rate control or heart failure management.
lovastatin + grapefruit
Grapefruit juice blocks intestinal CYP3A4, dramatically increasing lovastatin and lovastatin acid exposure. A controlled study showed lovastatin Cmax rose ~12-fold and AUC ~15-fold after high-dose grapefruit juice, sharply raising the risk of myopathy and rhabdomyolysis.
sertraline + st. john's wort
Sertraline is an SSRI that blocks serotonin reuptake, and St. John's wort independently inhibits serotonin reuptake and contains constituents (hyperforin, hypericin) that elevate central serotonin. Combining them can trigger serotonin syndrome, a potentially life-threatening syndrome of altered mental status, autonomic instability, and neuromuscular hyperactivity. St. John's wort also induces CYP3A4 and CYP2C19, which can lower sertraline plasma levels and undermine treatment.
cyclosporine + st. john's wort
St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein, which dramatically accelerates cyclosporine metabolism and efflux. Co-administration reduces cyclosporine blood AUC by roughly 40-50%, producing subtherapeutic levels that have caused documented acute organ rejection in heart, kidney, and liver transplant recipients.
tramadol + st. john's wort
Tramadol inhibits serotonin and norepinephrine reuptake, and St. John's Wort increases central serotonergic activity, so combining them raises the risk of serotonin syndrome. St. John's Wort also induces CYP3A4 and CYP2B6, which can reduce tramadol's active M1 metabolite and weaken analgesia.
tacrolimus + grapefruit
Grapefruit furanocoumarins irreversibly inhibit intestinal CYP3A4, increasing tacrolimus AUC by roughly 28% and Cmax by up to 73%. Case reports describe trough levels tripling after grapefruit ingestion, producing nephrotoxicity and neurotoxicity.
oxycodone + st. john's wort
St. John's Wort strongly induces CYP3A4, the main enzyme that metabolizes oxycodone. In a controlled crossover trial, St. John's Wort cut oral oxycodone plasma exposure (AUC) by roughly 50% and significantly reduced its analgesic effect.
oral contraceptives + st. john's wort
St. John's Wort induces CYP3A4 and P-glycoprotein, which accelerates the metabolism of ethinyl estradiol and progestins in combined oral contraceptives. Clinical trials have documented breakthrough bleeding and reduced contraceptive hormone exposure when the two are combined, raising the risk of ovulation and unintended pregnancy.
ketoconazole + st. john's wort
St. John's Wort is a potent inducer of CYP3A4 and P-glycoprotein via PXR activation, which can accelerate the metabolism of ketoconazole and reduce its antifungal blood concentrations and clinical effectiveness.
fluconazole + grapefruit
Fluconazole is a moderate inhibitor of CYP3A4 and grapefruit juice inhibits intestinal CYP3A4; the inhibition is additive, which can raise plasma levels of any third drug that depends on CYP3A4 for clearance.
atorvastatin + vitamin d
Vitamin D's active metabolite (calcitriol) can induce CYP3A4, which metabolizes atorvastatin. Small studies show vitamin D supplementation may reduce atorvastatin and metabolite plasma levels by up to ~55%, although LDL-lowering efficacy appears largely preserved.
simvastatin + berberine
Simvastatin is extensively metabolized by CYP3A4, and berberine inhibits CYP3A4 in vitro, which can raise simvastatin levels and increase the risk of myopathy and rhabdomyolysis. The interaction is bidirectional in some models (induction is also possible), making net effect unpredictable.
simvastatin + st. john's wort
St. John's wort induces intestinal and hepatic CYP3A4 and P-glycoprotein, sharply increasing simvastatin's first-pass metabolism. In a crossover study of healthy adults, the AUC of active simvastatin hydroxy acid was cut roughly in half (to about 48% of placebo).
grapefruit + sildenafil
Sildenafil is metabolized primarily by CYP3A4. Grapefruit juice inhibits intestinal CYP3A4 and modestly increases sildenafil AUC by about 23 percent while delaying peak concentration, which can worsen the headache, flushing, dizziness, and hypotension typical of PDE5 inhibitors.
amlodipine + grapefruit
Amlodipine is a CYP3A4 substrate, but unlike other dihydropyridines (felodipine, nisoldipine), its high oral bioavailability and slow elimination mean grapefruit juice does not meaningfully alter its pharmacokinetics in controlled trials. Some product labels and consumer references still list a theoretical interaction.
diltiazem + grapefruit
Grapefruit juice inhibits intestinal CYP3A4 and increases diltiazem exposure (AUC) by roughly 20% in healthy volunteers, with high inter-individual variability. The increase can amplify the drug's negative chronotropic and hypotensive effects.
grapefruit + carbamazepine
Grapefruit juice irreversibly inhibits intestinal CYP3A4, reducing first-pass metabolism of carbamazepine and increasing its bioavailability. Clinical study in epilepsy patients showed AUC rose by roughly 40 percent with concomitant grapefruit juice, pushing plasma levels toward the toxic range.
pomelo + tacrolimus
Pomelo contains furanocoumarins that inhibit intestinal CYP3A4 and P-glycoprotein, the two systems that limit tacrolimus absorption. A documented case in a renal transplant patient showed pomelo consumption nearly doubled tacrolimus blood levels, risking nephrotoxicity and neurotoxicity given tacrolimus's narrow therapeutic window.
grapefruit + methadone
Methadone is partially metabolized by CYP3A4 (and CYP2B6). Grapefruit juice inhibits intestinal CYP3A4 and can raise methadone plasma concentrations, with case reports of opioid toxicity after sustained grapefruit juice intake. Higher methadone levels also increase the risk of QT prolongation and torsades de pointes.
grapefruit + oxycodone
Oxycodone undergoes CYP3A4-mediated metabolism to noroxycodone. A controlled crossover study in healthy volunteers showed grapefruit juice increased oxycodone AUC 1.7-fold, peak concentration 1.5-fold, and half-life 1.2-fold, while reducing formation of inactive noroxycodone, raising the risk of sedation and respiratory depression.
seville orange + atorvastatin
Seville (bitter) orange contains the same furanocoumarins as grapefruit, including bergamottin and 6',7'-dihydroxybergamottin, which irreversibly inhibit intestinal CYP3A4. A landmark crossover study showed Seville orange juice raised felodipine AUC by 76%, comparable to grapefruit, and atorvastatin shares the same CYP3A4 metabolic pathway, raising the risk of statin-induced myopathy.
seville orange + cyclosporine
Seville orange juice contains furanocoumarins that reduce enterocyte CYP3A4 expression by approximately 40%, although a controlled human study found no significant change in cyclosporine AUC, likely because cyclosporine disposition also depends on intestinal P-glycoprotein, which Seville orange does not inhibit as strongly as grapefruit.
blood orange + simvastatin
Blood orange (Citrus sinensis var.) is a sweet orange and does not contain the furanocoumarins (bergamottin, 6',7'-dihydroxybergamottin) that drive the grapefruit-statin interaction. Published reviews of citrus furanocoumarin content list blood orange among the sweet oranges as essentially free of clinically significant CYP3A4-inhibiting compounds.
cranberry + tacrolimus
Cranberry juice has been shown to inhibit intestinal CYP3A enzymes, and tacrolimus is heavily metabolized by intestinal CYP3A4 and CYP3A5. The expected direction is an increase in tacrolimus trough levels, raising the risk of nephrotoxicity and tremor, although published cases are scarce and one case unexpectedly reported a decrease.
pomegranate + statins
Pomegranate juice inhibits intestinal CYP3A4, the main enzyme that metabolizes simvastatin, atorvastatin, and lovastatin. A published case report links pomegranate juice consumption to rhabdomyolysis in a patient stable on rosuvastatin, and the same enzyme inhibition can raise the systemic exposure and muscle toxicity risk of CYP3A4-metabolized statins.
amiodarone + grapefruit
Grapefruit juice inhibits intestinal CYP3A4, raising oral amiodarone AUC by approximately 50% and peak levels by 84% while abolishing production of its active metabolite N-desethylamiodarone. The FDA-approved Pacerone label explicitly states grapefruit juice should not be consumed during oral amiodarone treatment.
venlafaxine + st. john's wort
Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI). St. John's wort independently inhibits serotonin (and to a lesser extent norepinephrine and dopamine) reuptake. Combining them can drive a sharp rise in synaptic serotonin and trigger serotonin syndrome, and St. John's wort can also alter venlafaxine pharmacokinetics through CYP3A4 induction.
cbd + tacrolimus
CBD inhibits CYP3A4, CYP3A5, and P-glycoprotein, the main pathways that clear tacrolimus. A published case report documented an approximately 3-fold rise in dose-normalized tacrolimus levels after adding CBD, posing serious nephrotoxicity, neurotoxicity, and over-immunosuppression risk in transplant patients.
cbd + simvastatin
Simvastatin is heavily dependent on CYP3A4 for first-pass and systemic clearance, and CBD inhibits CYP3A4. Co-administration is expected to raise simvastatin and active-metabolite exposure, increasing the risk of muscle pain, transaminase elevation, and rare rhabdomyolysis.
grapefruit + lurasidone
Lurasidone is primarily metabolized by CYP3A4 and is highly sensitive to CYP3A4 inhibitors. The FDA-approved Latuda prescribing information specifically states that grapefruit and grapefruit juice should be avoided in patients taking lurasidone because they inhibit CYP3A4 and can substantially raise lurasidone concentrations.
phenytoin + vitamin d
Phenytoin induces hepatic CYP3A4 and CYP24A1, accelerating conversion of 25-hydroxyvitamin D to inactive metabolites and lowering circulating 25(OH)D, which over time produces secondary hyperparathyroidism, reduced calcium absorption, and a measurably increased risk of osteomalacia and fractures.
grapefruit + quetiapine
Quetiapine is metabolized primarily by CYP3A4. Grapefruit juice inhibits intestinal CYP3A4 and can substantially increase quetiapine plasma concentrations; a documented case report describes quetiapine toxicity in a young woman who consumed a gallon of grapefruit juice over 24 hours while on a stable dose.
bergamot + statins
Bergamot orange (Citrus bergamia) is the source of bergamottin, the prototype furanocoumarin that irreversibly inhibits CYP3A4. Bergamot juice and high-dose bergamot polyphenol supplements (BPF), often marketed for cholesterol, can theoretically raise levels of CYP3A4-metabolized statins (simvastatin, atorvastatin, lovastatin), though human pharmacokinetic data with statins are limited.
carbamazepine + vitamin d
Carbamazepine activates the pregnane X receptor and strongly induces hepatic CYP3A4 and CYP24A1, accelerating catabolism of 25-hydroxyvitamin D into inactive metabolites; meta-analyses confirm consistently lower 25(OH)D in long-term users along with secondary hyperparathyroidism and reduced bone mineral density.
omeprazole + st. john's wort
St. John's wort potently induces CYP3A4 and CYP2C19, the enzymes responsible for omeprazole metabolism. Co-administration significantly lowers omeprazole plasma concentrations, reducing its acid-suppressing efficacy and potentially compromising treatment of GERD, ulcers, or H. pylori eradication.
cyclosporine + grapefruit
Grapefruit juice contains furanocoumarins that irreversibly inhibit intestinal CYP3A4, raising cyclosporine bioavailability by 35-60% and increasing the risk of nephrotoxicity, hypertension, and neurotoxicity. The effect can persist for 24 hours or longer after a single glass.
atorvastatin + st. john's wort
St. John's wort potently induces hepatic and intestinal CYP3A4, accelerating atorvastatin's first-pass metabolism. A controlled study showed roughly a 12% drop in atorvastatin AUC and meaningful increases in LDL and total cholesterol over 4 weeks of co-administration.
pomegranate + warfarin
Pomegranate juice contains punicalagins and other polyphenols that inhibit CYP2C9 and CYP3A4 in vitro, which would slow warfarin metabolism. Case reports describe both elevated INR (one patient reached INR 14 after heavy consumption) and subtherapeutic INR after stopping habitual juice intake.
escitalopram + st. john's wort
Escitalopram is a highly selective SSRI metabolized largely by CYP2C19 and CYP3A4. St. John's wort independently inhibits serotonin reuptake and strongly induces these same enzymes plus P-glycoprotein. Combined use risks serotonin syndrome and can also lower escitalopram plasma levels, blunting its antidepressant effect.
carbamazepine + st. john's wort
Both carbamazepine and St. John's Wort are strong inducers of CYP3A4, the enzyme that primarily metabolizes carbamazepine. Although healthy-volunteer studies have shown limited additional effect on chronic carbamazepine kinetics (because carbamazepine already maximally autoinduces its own metabolism), starting or stopping St. John's Wort can destabilize carbamazepine levels, and the herb can lower exposure to single carbamazepine doses by up to 21% before autoinduction is established.
raloxifene + st. john's wort
Although raloxifene is cleared primarily by glucuronidation rather than CYP3A4, St. John's Wort induces P-glycoprotein and other transporters that may reduce raloxifene exposure. Drug interaction databases list a documented reduction in raloxifene serum concentration with concurrent use, potentially undermining osteoporosis treatment.
tacrolimus + st. john's wort
St. John's wort induces CYP3A4 and P-glycoprotein, slashing tacrolimus blood concentrations and risking acute graft rejection. Conversely, abrupt discontinuation of the herb can unmask tacrolimus nephrotoxicity as levels rebound.
pomelo + simvastatin
Pomelo (Citrus maxima) contains furanocoumarins that irreversibly inhibit intestinal CYP3A4, the enzyme that metabolizes simvastatin during first-pass absorption. With CYP3A4 disabled, simvastatin plasma concentrations rise substantially, increasing the risk of myopathy and rhabdomyolysis.
thc + benzodiazepines
THC and benzodiazepines are both central-nervous-system depressants and produce additive sedation, ataxia, cognitive impairment, and respiratory slowing. THC and CBD components of cannabis also inhibit CYP3A4, which metabolizes alprazolam, midazolam, and triazolam, potentially raising benzodiazepine plasma levels.
grapefruit + sirolimus
Sirolimus is a CYP3A4 and P-glycoprotein substrate with a narrow therapeutic window and high baseline interpatient variability. The FDA-approved Rapamune label states that grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus and must not be taken with or used to dilute the drug, because unpredictable, large rises in blood levels can cause nephrotoxicity, infection, and graft injury.
black pepper + propranolol
Piperine, the active alkaloid in black pepper, inhibits CYP3A4, CYP2C9, and intestinal P-glycoprotein, increasing the oral bioavailability and serum concentration of propranolol and other beta-blockers, which can amplify blood pressure and heart rate reduction.
alprazolam + grapefruit
Grapefruit juice contains furanocoumarins that inhibit intestinal CYP3A4, the enzyme that partially metabolizes alprazolam. The interaction can raise alprazolam blood levels and prolong sedation, although the magnitude is modest compared to other benzodiazepines because alprazolam has high oral bioavailability.
atorvastatin + berberine
Berberine inhibits CYP3A4 in vitro and can raise plasma levels of CYP3A4 substrates, including atorvastatin, which may increase the risk of muscle pain, liver enzyme elevation, and rhabdomyolysis. The interaction direction is complex — some animal data also show induction — but co-use is unpredictable.
grapefruit + buspirone
Buspirone undergoes extensive first-pass metabolism by intestinal and hepatic CYP3A4. A controlled study showed grapefruit juice increased buspirone AUC 9.2-fold and peak plasma concentration 4.3-fold, dramatically amplifying sedation, dizziness, and serotonergic effects.