Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review

Abstract

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.

UGT2B7 c.-161C>T polymorphism frequency in Croatian population

“…Future research should also put more focus on the association between substrate metabolism and the UGT2B7 c.-161C>T polymorphism and its genotype distribution in different conditions associated with this variant (e.g. oxidative stress, hypertension, atherosclerosis, renal disease, cancer) ( 20 , 21 , 35 , 38 , 39 , 40 , 41 ). As the activity of UGT2B7 encoded by the c .- 161C>T variant allele carriers is substrate-specific and confirmed for different drugs, further research should also focus on examining the clinical relevance of this polymorphism for other substrate drugs such as fenofibrates.…”

“…Genetic association studies indicate that the UGT2B7*2 polymorphism has an important role in moderating both pharmacokinetic and pharmacodynamic properties of substrate drugs due to lower enzyme activity and glucuronidation rate. In addition, this polymorphism moderates toxic and/or carcinogenic effects of other endogenous and exogenous substrate metabolites and may have a part in disease pathogenesis ( 19 ), including vasoconstriction, hypertension, atherosclerosis, and renal injury through lower glucuronidation of 20-hydroxyeicosatetraenoic acid (20-HETE) ( 20 , 21 ).…”

“…The aim of this study was to complement our earlier genotyping research of the UGT2B7 c.-161C>T (rs7668258) polymorphism (and consequently of the rs7439366 variant) in the Croatian population as this specific polymorphism is in strong linkage disequilibrium (LD) with UGT2B7*2 (rs7439366)variant ( 21 , 28 ) and has a considerable impact on the pharmacokinetics of lamotrigine ( 29 , 30 , 31 , 32 ). In view of the cases in clinical practice, we believe its genotypes may result in variable kinetics and predisposition to side effects of several substrate drugs ( 21 , 32 ). Our secondary aim was to compare its genotype frequencies with other ethnicities in Europe and worldwide.…”

Topical Diclofenac-Induced Hepatotoxicity

“… 28 The proposed idiosyncratic mechanisms by which the drug harms the liver at the cellular level include individual allelic variants of UGT2B7, CYP2C8, and ABCC2, which can lead to accumulation of reactive metabolites (diclofenac acyl glucuronides), resulting in formation of unstable adducts and inappropriate immune responses. 4 , 7 , 21 , 29 …”