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Pharmacology: Pharmacodynamics: Tolvaptan is a selective vasopressin V2-receptor antagonist. Antagonism of vasopressin causes an increase in urine water excretion resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.
Pharmacokinetics: Absorption: Tmax: 1.75 to 4 hours.
Bioavailability: 40%; Absolute bioavailability decreases with increasing doses. Following an oral dose of 30 mg, absolute bioavailability was 56% (range, 42% to 80%).
Effects of food: No effect.
Distribution: Vd: 3 L/kg.
Protein binding: Greater than 98%, to albumin and alpha 1-acid glycoprotein.
Metabolism: Hepatic: Almost exclusively via CYP3A.
Substrate of CYP3A.
Substrate and inhibitor of P-glycoprotein.
Inhibitor of OATPI Bl/B3 and OAT3.
Inhibitor of Breast Cancer Resistance Protein.
Excretion: Renal excretion: 40%, almost all as metabolites.
Fecal excretion: 59%, with 19% as unchanged drug.
Total body clearance: 35.6 to 38.7 L/hr; 4 mL/min/kg (healthy volunteers); 2 mL/min/kg (hyponatremic patients).
Elimination Half Life: 2.8 to 12 hours.
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