Summary

Ketoconazole significantly increases quetiapine blood levels by inhibiting the CYP3A4 enzyme responsible for quetiapine metabolism. This interaction can lead to enhanced quetiapine side effects and requires careful dose adjustments and monitoring.

Introduction

Quetiapine (brand name Seroquel) is an atypical antipsychotic medication primarily used to treat schizophrenia, bipolar disorder, and major depressive disorder as an adjunct therapy. It belongs to the dibenzothiazepine class of antipsychotics and works by modulating dopamine and serotonin receptors. Ketoconazole is a potent antifungal medication from the azole class, used to treat serious fungal infections. It is a strong inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, which is responsible for metabolizing many medications including quetiapine.

Mechanism of Interaction

The interaction between quetiapine and ketoconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Quetiapine is extensively metabolized by CYP3A4 in the liver, with this pathway accounting for the majority of its clearance from the body. When ketoconazole is co-administered, it potently inhibits CYP3A4 activity, significantly reducing quetiapine's metabolism and clearance. This results in substantially increased plasma concentrations of quetiapine, potentially leading to a 3-5 fold increase in drug exposure and prolonged elimination half-life.

Risks and Symptoms

The primary clinical risk of this interaction is the development of enhanced quetiapine-related adverse effects due to elevated drug concentrations. Patients may experience increased sedation, dizziness, orthostatic hypotension, and extrapyramidal symptoms. More serious risks include QT interval prolongation, which can lead to potentially fatal cardiac arrhythmias, particularly torsades de pointes. Other concerning effects may include severe hypotension, respiratory depression, and increased risk of metabolic side effects such as hyperglycemia and weight gain. Elderly patients and those with pre-existing cardiac conditions are at particularly high risk for serious complications.

Management and Precautions

When co-administration is necessary, quetiapine dosage should be reduced to approximately one-sixth of the original dose to account for the increased exposure. Close monitoring is essential, including regular assessment of vital signs, cardiac monitoring with ECGs to evaluate QT interval, and observation for signs of quetiapine toxicity. Alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole or terbinafine, should be considered when clinically appropriate. If ketoconazole must be used, initiate with the lowest effective quetiapine dose and titrate slowly based on clinical response and tolerability. Patients should be counseled about potential increased side effects and advised to report any concerning symptoms immediately.

Quetiapine interactions with food and lifestyle

Quetiapine should not be taken with alcohol as it can increase the risk of drowsiness, dizziness, and impaired coordination. Grapefruit juice may increase quetiapine levels in the blood and should be avoided. Patients should be cautious when driving or operating machinery due to potential sedation effects. Smoking may decrease quetiapine effectiveness, and patients should discuss smoking cessation with their healthcare provider.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.