Absorption, Distribution, Metabolism and Excretion of [14C]Dexlansoprazole in Healthy Male Subjects

Abstract

The proton pump inhibitor dexlansoprazole is a modified-release formulation of dexlansoprazole, an enantiomer of lansoprazole, which employs a Dual Delayed Release™ (DDR) delivery system. This study was conducted in healthy subjects to assess the absorption, distribution, metabolism and excretion of a 60 mg dose of [14C]dexlansoprazole. After multiple daily doses of dexlansoprazole DDR for 4 days followed by a single dose of [14C]dexlansoprazole on day 5, absorption, distribution, metabolism and elimination of [14C]dexlansoprazole were assessed in six healthy male subjects whose CYP (cytochrome P450) 2C19 metabolizer status was also determined. Five subjects were phenotyped as extensive metabolizers (EMs) and one subject was a poor metabolizer (PM). Recovery of radioactivity in urine and faeces averaged 98% after 7 days (51% in urine and 48% in faeces) post-14C dosing. In plasma, dexlansoprazole was the largest component detected, with the main metabolites in the EM subjects being 5-glucuronyloxy dexlansoprazole and 5-hydroxy dexlansoprazole (CYP2C19 mediated), whereas the PM subject had greater amounts of dexlansoprazole sulfone (CYP3A mediated). Dexlansoprazole was not detected in urine; six metabolites were identified accounting for an average of 86% of the urinary radioactivity, with 5-glucuronyloxy dexlansoprazole, 5-glucuronyloxy dexlansoprazole sulfide, 2-S-N-acetylcysteinyl benzimidazole and 5-sulfonyloxy dexlansoprazole sulfide being the primary metabolites. In faeces, parent drug and six identified metabolites accounted for 23% and 72%, respectively, of the faecal radioactivity, with 5-hydroxy dexlansoprazole sulfide and dexlansoprazole sulfide being predominant. Overall, the results indicate that [14C]dexlansoprazole was well absorbed and extensively metabolized by oxidation, reduction and conjugation to 13 identified metabolites.