IMPACT OFCYP2C9GENOTYPE ON PHARMACOKINETICS: ARE ALL CYCLOOXYGENASE INHIBITORS THE SAME?: TABLE 1

Abstract

ABSTRACT:The market withdrawals of rofecoxib (Vioxx) and valdecoxib (Bextra) have focused considerable attention on the side effect profiles of cyclooxygenase (COX) inhibitors. As a result, attempts will be made to identify risk factors in the hope that physicians might be able to ensure patient safety. At first glance, CYP2C9 genotype might be considered a risk factor because many COX inhibitors are CYP2C9 substrates in vitro. This observation has led some to hypothesize that a reduction in clearance, in subjects expressing variant forms of the enzyme (e.g., CYP2C9*1/*3 or CYP2C9*3/*3 genotype), will lead to increased exposure and a greater risk of cardiovascular or gastrointestinal side effects. For any drug, however, one has to consider all clearance pathways. Therefore, a number of COX inhibitors were surveyed and it was determined that CYP2C9 plays a relatively minor role in the overall clearance (<20% of the dose) of sulindac, naproxen, ketoprofen, diclofenac, rofecoxib, and etoricoxib. CYP2C9 genotype would have no clinically meaningful impact on the pharmacokinetics of these drugs. In contrast, CYP2C9 genotype is expected to impact the clearance of ibuprofen, indomethacin, flurbiprofen, celecoxib, valdecoxib, lornoxicam, tenoxicam, meloxicam, and piroxicam. However, even when CYP2C9 is a major determinant of clearance, it is necessary to consider CYP2C8 genotype (e.g., ibuprofen) and, possibly, CYP3A4 activity (e.g., celecoxib, valdecoxib, and meloxicam) also.Events surrounding the market withdrawal of rofecoxib (Vioxx), a potent and selective COX-2 inhibitor, have raised concerns about the safety of other COX-2 selective inhibitors such as etoricoxib (Arcoxia), celecoxib (Celebrex), lumiracoxib (Prexige), and valdecoxib (Bextra) (Mukherjee et al., 2002;Bing, 2003;Couzin, 2004;Davies and Jamali, 2004;Fitzgerald, 2004;Kim and Reicin, 2004;Ray et al., 2004;Scheen, 2004;Bannwarth, 2005;Berenbaum, 2005). Such concerns finally resulted in the withdrawal of valdecoxib about seven months after the withdrawal of rofecoxib (Lenzer, 2005;Young, 2005). Nonselective COX inhibitors (NSAIDs) like naproxen, diclofenac, and ibuprofen have also come under scrutiny from regulators, physicians, and patient safety advocacy groups (McGettigan and Henry, 2000;Meagher, 2003).At the present time, it is thought that the CV and GI side effects of COX inhibitors are related to their mechanism of action. This involves the inhibition of COX, a hemeprotein that exists in two forms (COX-1 and COX-2). COX-1 is expressed constitutively in most tissues, whereas the expression of COX-2 can be induced by growth factors, cytokines, and vasoactive peptides such as endothelin. In response to cell damage, therefore, COX-2 is inducible by proinflammatory mediators and plays a role in the generation of prostaglandin E 2 , a major mediator of inflammatory response. On the other hand, the products of COX-1 are cytoprotective in GI epithelium, and selective inhibition of COX-2 is anticipated to reduce inflammation, and modulate pain, without the GI...

Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro

“…At a higher IBU concentration (500 M), the same inhibitors were less able to inhibit the 2-hydroxylation of There has been continued interest in the safety and ADME properties of cyclooxygenase inhibitors. This interest has extended to 2-(4-isobutylphenyl)propionic acid (ibuprofen, IBU), which is administered as a racemic mixture of (S)-(ϩ)-and (R)-(Ϫ)-enantiomers (Rodrigues, 2005;Agúndez et al, 2007;Pilotto et al, 2007;Blanco et al, 2008). The metabolism of both enantiomers is complex and involves direct (acyl) glucuronidation, 2-hydroxylation, and 3-hydroxylation (methyl hydroxylation) (Fig.…”

Pharmacogenetics of nonsteroidal anti-inflammatory drugs

“…39 Researchers have assessed the role of CYP2C9 in the overall clearance of indomethacin and have determined that its role is substantial regarding the clearance of indomethacin. 40 There was no significant difference in the AUC for indomethacin in patients experiencing gastrointestinal bleeding compared with those without bleeding. 41 An additional study assessed the frequency of the CYP2C9 variation among 20 þ individuals with a past medical history of NSAIDrelated gastric ulceration versus 30 þ individuals who did not have a history of gastropathy.…”

“…18 However, another study assessed the role of CYP2C9 in the overall clearance of naproxen and concluded that CYP2C9 played a minor role in naproxen clearance, suggesting that pharmacogenetic differences would not be clinically significant if compromised CYP2C9 activity was possessed by a patient taking this medication. 40 Furthermore, there was no significant difference between the C max and AUC for naproxen in patients experiencing gastrointestinal bleeding compared with those without bleeding from two studies. 41,42 The subsequent frequency of CYP2C9 genotype was comparable to that of subjects with a history of gastric ulcers associated with NSAID use and those receiving NSAIDs minus the gastric ulceration.…”

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

“…CYP450 rather than glucuronidation) is more plausible in our opinion, as signiWcant pharmacogenomic diVerences have also been described for this system within humans (Rodrigues 2005). CYP450 pharmacogenomic diVerences within G. coprotheres (as opposed to a total deWciency in the glucoronidation pathway) would explain why only 7 of the 11 animals died following dosing at the same level (5 mg/kg).…”

“…However, in studies on the pharmacokinetics of meloxicam, Naidoo et al (2008a) described the presence of a glucoronide and hydroxyl metabolite, thereby indicating that the metabolism of meloxicam at least, in Gyps vultures, is potentially similar to that found in mammals (Naidoo et al 2008a;Lees 2009). In the recognised metabolic pathways described for mammals, the presence of the hydroxyl metabolite indicates the involvement of the cytochrome P450 (CYP450) enzyme system, whilst the glucoronide metabolite indicates the involvement of the UDP glycosyltransferase enzyme (Rodrigues 2005). At this stage, it is plausible that either of these enzymatic processes may enforce the rate limiting step in the metabolic transformation of ketoprofen.…”