Newer NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects.Several COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn from the market, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining the microvasculature in the body are proposed to express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (specifically, PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference as compared with reversible inhibitors. Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins, converts this enzymes activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase-like enzyme: aspirin-treated COX-2 metabolizes a variety of polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to specialized proresolving mediators such as the aspirin-triggered lipoxins, aspirin-triggered resolvins, and aspirin-triggered maresins. These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin. Additional mechanisms
Aspirin has been shown to have at least three additional modes of action.
Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation is another risk factor for increased toxicity

De-conjugation by β-glucuronidases
The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38. Metabolism by cytochrome P450 enzymes
Irinotecan is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC can be further converted by CES1 and CES2 in the liver to SN-38. Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with irinotecan. Transport to bile
Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2. Elimination
Irinotecan clearance is mainly biliary (66%) and estimated 12–21 L/h/m2. All metabolites, except SN-38G, are mainly excreted in feces. Irinotecan  elimination half-lives were reported between 5 to18 h. SN-38 half-lives were reported between  6 and 32 h.There is high (30%) interindividual variability in irinotecan pharmacokinetic parameters which can be altered by several factors including age, sex, dose, administration timing, hepatic function, enzyme activity or hematocrit levels. Pharmacogenomics
Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation. *28 variant patients
People with variants of the UGT1A1 called TA7, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often have Gilberts syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others.