Intestinal Metabolism of Diclofenac by Polymorphic UGT2B17 Correlates with its Highly Variable Pharmacokinetics and Safety across Populations

Abstract

Although the United States and Europe have shifted to the prescription use of oral diclofenac due to several serious incidences of cardiotoxicity, it is one of the most commonly used over‐the‐counter (OTC) pain medicines in major parts of the world. We elucidated the quantitative and tissue‐specific contribution of uridine diphosphate‐glucuronosyltransferases 17 (UGT2B17) in diclofenac metabolism and pharmacokinetics (PK). UGT2B17 is one of most deleted genes in humans with the gene deletion frequency ranging from ~ 20% in White population to 90% in Japanese population. The human intestinal and liver microsomes isolated from the high‐UGT2B17 expressing individuals showed 21‐ and 4‐fold greater rate of diclofenac glucuronide (DG) formation than in the null‐UGT2B17 carriers, respectively. The greater contribution of intestinal UGT2B17 was confirmed by a strong correlation (R = 0.78, P < 0.001) between UGT2B17 abundance and DG formation in individual intestinal microsomes (n = 14). However, because UGT2B17 is a minor UGT isoform in the liver, DG formation rate correlated better with the expression of UGT2B7. The proteomics‐informed physiologically‐based pharmacokinetic (PBPK) model explains the reported higher exposure of diclofenac in women consistent with ~ 3‐fold lower expression of UGT2B17. Similarly, our in silico predictions also corroborate with the reported higher exposure and lower standard clinical dose of diclofenac in Japanese population. Therefore, variable UGT2B17 mediated metabolism of oral diclofenac is a cause of concern, especially in the developing countries where it is still used as an OTC drug. The ontogeny data of UGTs in human hepatocytes can be utilized in developing PBPK models for predicting PK in the pediatric population.