Pharmacokinetics and metabolism of all-trans-and 13-cis-retinoic acid in pulmonary emphysema patients

Josephia R. Muindi, Michael D. Roth, Robert A. Wise, John E. Connett, George T. O'Connor, Joe W. Ramsdell, Neil W. Schluger, Marjorie Romkes, Robert A. Branch, Frank C. Sciurba

Research output: Contribution to journalArticlepeer-review

Abstract

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 Cmax 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 Cmax (<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.

Original languageEnglish (US)
Pages (from-to)96-107
Number of pages12
JournalJournal of clinical pharmacology
Volume48
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • 13-cRA
  • ATRA
  • Emphysema
  • Metabolism
  • Plasma pharmacokinetics
  • Retinoid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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