Unduly Enhanced Response to Tolvaptan in a Woman Showing Syndrome of Inappropriate Antidiuretic Hormone Secretion: An Investigation of Possible Causes

Abstract

ABSTRACT: Objective: To investigate possible causes of an excessive response to tolvaptan in a woman with syndrome of inappropriate antidiuretic hormone secretion (SIADH).Methods: A 32-year-old woman was admitted to our cardiologic unit 3 months after delivery for hypertension and severe hyponatremia (120 mEq/L). Two hyponatremic episodes had already been documented in her medical history. SIADH was diagnosed and treatment with tolvaptan, an arginine vasopressin (AVP) antagonist, was instituted. After the first 15-mg dose, excessive polyuria (1 L/hour) and a rapid increase in serum sodium (13 mEq/L in 8 hours) occurred, so that therapy was stopped and restarted 2 days later at a reduced dose (5 mg). This level was effective and well tolerated. To explore the possible pharmacokinetic and pharmacodynamic mechanisms underlying the patient's hyperresponsiveness, the following tests were carried out: (1) in vivo phenotyping of CYP3A4 activity, the cytochrome responsible for tolvaptan metabolism, with two probe drugs (omeprazole and dextromethorphan); and (2) search for mutations in genes involved in AVP signaling (AVP, V2R, AQP2, OXT).Results: Neither phenotyping nor genotyping tests evidenced abnormalities capable of explaining the patient's enhanced response to tolvaptan, in that: (1) CYP3A4 activity was normal-to-high; and (2) genes coding for AVP, vasopressin-2 receptor, aquaporin-2, and oxytocin did not show any mutations.Conclusion: This study excluded many, but not all, possible causes of hyperresponsiveness to tolvaptan. Two hypotheses concerning pretreatment AVP levels in SIADH patients are suggested to address future research.Abbreviations: 3MM 3-methoxy-morphinan; AQP2 aquaporin-2 water channel; AVP arginine vasopressin; CYP3A4 cytochrome P450 CYP3A4; DMT dextromethorphan; OME omeprazole; OXT oxytocin; SIADH syndrome of inappropriate antidiuretic hormone secretion; SUL omeprazole sulfone; V2R vasopressin type 2 receptor