Summary

Cyclosporine significantly increases repaglinide plasma concentrations through CYP2C8 inhibition, leading to enhanced hypoglycemic effects. This interaction is considered clinically significant and may require dose adjustments or alternative therapy selection.

Introduction

Cyclosporine is a potent immunosuppressive agent belonging to the calcineurin inhibitor class, primarily used to prevent organ transplant rejection and treat autoimmune conditions. Repaglinide is a meglitinide antidiabetic medication that stimulates insulin release from pancreatic beta cells, used for managing type 2 diabetes mellitus. Both medications are metabolized through hepatic pathways, creating potential for significant drug interactions.

Mechanism of Interaction

The interaction occurs through cyclosporine's potent inhibition of cytochrome P450 2C8 (CYP2C8), the primary enzyme responsible for repaglinide metabolism. Cyclosporine blocks the hepatic clearance of repaglinide, resulting in increased plasma concentrations and prolonged half-life of the antidiabetic medication. This pharmacokinetic interaction can increase repaglinide exposure by up to 2.4-fold, significantly enhancing its glucose-lowering effects and duration of action.

Risks and Symptoms

The primary clinical risk is severe and prolonged hypoglycemia due to elevated repaglinide concentrations. Patients may experience symptoms including dizziness, confusion, sweating, tremors, and in severe cases, loss of consciousness or seizures. The risk is particularly elevated in elderly patients, those with renal or hepatic impairment, and individuals with irregular eating patterns. The prolonged duration of hypoglycemic effects may require extended monitoring and treatment with glucose supplementation.

Management and Precautions

Close monitoring of blood glucose levels is essential when these medications are used concurrently. Consider reducing repaglinide dose by 50% or more when initiating cyclosporine therapy. Alternative antidiabetic medications with different metabolic pathways, such as metformin or insulin, may be preferred. If combination therapy is necessary, frequent glucose monitoring, patient education about hypoglycemia symptoms, and readily available glucose sources are crucial. Healthcare providers should consider therapeutic drug monitoring and adjust dosing based on clinical response and glucose control.

Cyclosporine interactions with food and lifestyle

Cyclosporine has several important food and lifestyle interactions that patients should be aware of: **Grapefruit and Grapefruit Juice:** Avoid grapefruit and grapefruit juice while taking cyclosporine. Grapefruit contains compounds that inhibit CYP3A4 enzymes, which can significantly increase cyclosporine blood levels and potentially lead to toxicity. This interaction is well-documented and patients are specifically warned to avoid grapefruit products. **High-Fat Meals:** Taking cyclosporine with high-fat meals can increase the absorption of the medication, potentially leading to higher blood levels. While this doesn't require complete avoidance, patients should maintain consistent dietary habits and take cyclosporine at the same time each day relative to meals. **St. John's Wort:** This herbal supplement should be avoided as it can significantly decrease cyclosporine blood levels by inducing CYP3A4 enzymes, potentially leading to organ rejection in transplant patients or treatment failure. **Alcohol:** While moderate alcohol consumption may not be completely contraindicated, patients should discuss alcohol use with their healthcare provider as cyclosporine can affect liver function, and alcohol may compound these effects. **Sun Exposure:** Patients taking cyclosporine have an increased risk of skin cancer and should limit sun exposure, use sunscreen with high SPF, and wear protective clothing when outdoors.

Repaglinide interactions with food and lifestyle

Repaglinide should be taken with meals to optimize blood glucose control and reduce the risk of hypoglycemia. The timing of repaglinide administration is important - it should be taken within 30 minutes before each meal, and if a meal is skipped, the corresponding dose should also be skipped. Alcohol consumption may increase the risk of hypoglycemia when used with repaglinide, and patients should be counseled to monitor blood glucose levels closely if consuming alcohol. Grapefruit juice may potentially increase repaglinide levels and should be consumed with caution, though this interaction is not as well-established as with some other medications.