Pharmacokinetic and Pharmacodynamic Consequences of Liver‐Lung Crosstalk: Rethinking Dosing in Hepatopulmonary Syndrome and Portopulmonary Hypertension

ABSTRACT Pharmacokinetic and pharmacodynamic consequences of liver‐lung crosstalk in hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH), with a proposed dosing framework. In HPS (left), intrapulmonary vascular dilations cause right‐to‐left shunting, bypassing pulmonary first‐pass metabolism and increasing systemic drug exposure. In PoPH (right), right ventricular dysfunction reduces cardiac output, impairing hepatic and renal perfusion and decreasing clearance of flow‐dependent drugs. Both syndromes share cirrhosis‐related alterations: reduced CYP450 activity, hypoalbuminemia (increased free drug fraction), and portosystemic shunting. The lower panel outlines a stepwise clinical approach: (1) Child‐Pugh stratification, (2) free drug monitoring for select highly protein‐bound drugs, (3) consideration of cystatin C‐based eGFR, and (4) dose reduction (50%–75%) for flow‐dependent drugs in patients with severe PoPH (cardiac index < 2.2 L/min/m 2 ). Key principles: “low start, slow go,” avoid NSAIDs and strong CYP3A4 inducers/inhibitors, and monitor narrow therapeutic index drugs.