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 diphosphateglucuronosyltransferases 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.

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

“…However, UGT2B17 is highly polymorphic resulting in different expression levels of the encoded protein, 45 which can also be seen in the striking protein levels variability in the liver (CV, 162.6%) and jejunum (CV, 96.7%) as observed in our study. A very recent study has reported that the UGT2B17‐mediated intestinal metabolism of diclofenac correlates with its highly variable pharmacokinetics and safety 46 . Moreover, this genetic variability was discussed to be associated with various types of cancer, that is, genetic UGT2B17‐deletion was identified as risk factor for head, neck, and esophageal cancer, whereas it seems not to be associated with testosterone dependent tumors, such as prostate cancer 47,48 …”

“…A very recent study has reported that the UGT2B17mediated intestinal metabolism of diclofenac correlates with its highly variable pharmacokinetics and safety. 46 Moreover, this genetic variability was discussed to be associated with various types of cancer, that is, genetic UGT2B17-deletion was identified as risk factor for head, neck, and esophageal cancer, whereas it seems not to be associated with testosterone dependent tumors, such as prostate cancer. 47,48 With respect to CES, which were shown to be the most abundant of all investigated enzymes in the human intestine and liver, CES1 was significantly higher expressed on gene and protein levels in the liver than in the jejunum, whereas it was the opposite for CES2.…”

Experimental pharmacology in precision medicine

“…Considering the cardiotoxicity risk of diclofenac, proteomics-informed PBPK modeling suggests that the diclofenac dose should be decreased in women and the carriers of UGT2B17 gene deletion. 18 Similarly, quantitative proteomics is useful in the discovery and quantification of efficacy biomarkers. For example, warfarin is a narrow therapeutic index drug that requires stratification of subjects based on the levels of descarboxylated prothrombin.…”

“…UGT2B17 gene deletion carriers and women are vulnerable to slower metabolism and increased bioavailability of diclofenac. Considering the cardiotoxicity risk of diclofenac, proteomics‐informed PBPK modeling suggests that the diclofenac dose should be decreased in women and the carriers of UGT2B17 gene deletion 18 . Similarly, quantitative proteomics is useful in the discovery and quantification of efficacy biomarkers.…”