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Pharmacokinetics and Metabolism of All-trans- and 13-cis-Retinoic Acid in Pulmonary Emphysema Patients

From the Divisions of Pulmonary, Allergy and Critical Care Medicine (Dr Sciurba) and Clinical Pharmacology (Dr Muindi, Dr Romkes, Dr Branch), University of Pittsburgh, Pittsburgh, Pennsylvania; University of California, Los Angeles (Dr Roth); Boston University, Boston, Massachusetts (Dr O'Connor); University of California, San Diego (Dr Ramsdell); Columbia University, New York, New York (Dr Schluger); Johns Hopkins University, Baltimore, Maryland (Dr Wise); and the Division of Biostatistics, University of Minnesota, Minneapolis (Dr Connett).

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers—all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)—in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA C_max. However, at follow-up, plasma ATRA C_max was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C_max (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r² = –0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.

Key Words: ATRA • 13-cRA • plasma pharmacokinetics • metabolism • emphysema • retinoid

Address for reprints: Josephia R. Muindi, MD, PhD, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Street, Buffalo, NY 14263; e-mail: josephia.muindi{at}roswellpark.org.