Valdecoxib: PHARMACOLOGY

7 Jul
2010

Valdecoxib is a 4-[5-methyl-3-phenylisox-azol-4-yl]-benzenesulfonamide that works by selectively inhibiting the cyclooxygenase-2 enzyme. The process begins with a stimulus, either inflammatory or physiological, causing the release of arachidondic acid from cell membrane phospholipids. Arachidonic acid is converted to prostaglandins (PG) through the enzyme prostaglandin G/H synthase, also known as cyclooxygenase (COX) or hydroperoxidase (HOX), as seen in Figure 1. There are two types of COX enzymes that traditional NSAIDs inhibit: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Currently, there are no medications that selectively inhibit the activity of the HOX enzyme. The COX-1 enzyme is expressed in most body tissues (i.e., stomach, kidneys, platelets, and intestines) where it produces prostaglandins for physiological regulation of the body, or homeostatis. This includes gastrointestinal cytoprotection, maintenance of normal renal function, and platelet aggregation. Consequently, NSAIDs, which block the COX-1 enzyme, can cause gastrointestinal irritation and injury, antiplatelet effects and compromised renal function. By comparison, the COX-2 enzyme is expressed in lower levels at baseline in these tissues and are shown to be present in the brain, bones, female reproductive tract, and kidneys, and tends to be expressed in higher levels during an inflammatory process. With the use of the selective COX-2 inhibitors (or COX-1-sparing NSAID), patients can receive the same anti-inflammatory and analgesic effects as the traditional NSAIDs, sparing the adverse effects seen with the inhibition of COX-1. Studies show that valdecoxib and the others in its class do not inhibit the COX-1 enzyme at therapeutic concentrations.

PHARMACOKINETICS

Valdecoxib is available in an oral formulation in doses of 10 and 20 mg. The pharmacokinetic parameters of the COX-2 inhibitors differ slightly from one another (Table 4). Valdecoxib achieves maximal plasma concentrations within three hours, and within four days, it achieves steady-state plasma concentra-tions. Valdecoxib can be taken with or without food with no significant effects on the peak plasma concentration or oral absorption; however, the time to peak concentration might be delayed by one to two hours. Valdecoxib should be avoided in patients with hepatic and renal insufficiency. Serum concentrations in patients with moderate hepatic insufficiency were shown to increase over 100%. There were no changes in renal clearance in patients with compromised renal function receiving valdecoxib; however, because of the potential for NSAIDs to worsen renal failure through prostaglandin inhibition and increased sodium retention, valdecoxib should be avoided in these patients.

Figure 1 Mechanism of Action of COX-2 Inhibitors

Figure 1 Mechanism of Action of COX-2 inhibitors

Table 4 Pharmacokinetic Parameters of the COX-2 Inhibitors

Pharmacokinetic ParameterValdecoxibcialis professionalRofecoxib
Oral bioavailability (%)8322-4092-93
Plasma protein binding (%)~98>9786
Half life (hours)8-11~1110-17
Time to maximal plasma concentration (hours)      32-42-3
Effect of foodNoneNoneMinimal

The renal effects of valdecoxib have been compared to placebo and traditional NSAIDs in one clinical trial, which included approximately 1,000 patients with OA and RA. The incidence of renal effects was higher in the valdecoxib group (3% vs. 1% for placebo); however, when compared to ibuprofen (7%), cialis professional online (2%) and diclofenac (4%), the results were similar (3% for valdecoxib). All renal events were considered to have resulted from edema or worsening of blood pressure. Although a limited number of studies have been conducted comparing renal events of traditional NSAIDs with the other coxibs, the overall renal effects of the COX-2 inhibitors seem to be similar to those seen with traditional NSAIDs. Patients who are at an increased risk of a renal event (i.e., heart failure, renal or hepatic disease, those taking angiotensin-converting enzyme [ACE]-inhibitors or elderly patients) should be closely monitored.

top