Determinants and sources of variability in GI complications of COX-inhibitory drugs. (a) Major determinants of the likelihood of an upper GI bleeding (UGIB) complication resulting from administration of a COX inhibitor include pharmacokinetic (PK) and pharmacodynamic (PD) variables, as well as the interaction of the drug with pre-existing risk factors for UGIB. PK features, such as half-life of the drug, and PD features, such as its selectivity for the COX-2 isoform, are intrinsic to the COX inhibitor. The presence or absence of risk factors for UGIB will clearly vary between patients. Significant interindividual variability arises from several sources, as shown in b and c, and is superimposed on each of these effects. Modified from ref. 2. (b) In addition to the variable plasma levels achieved after oral dosing of a COX inhibitor, the inhibition of the platelet COX-1 isozyme (circles) and the monocyte COX-2 isozyme (triangles) in response to any given plasma level of the inhibitor is highly variable between subjects. COX-isozyme inhibition, measured ex vivo, is plotted as a function of plasma meloxicam levels in individual subjects. Modified from ref. 31. (c) The variable excess of UGIB induced by NSAIDs as a function of the increasing severity of prior history: 1, none; 2, dyspepsia; 3, gastritis; 4, uncomplicated ulcer; 5, complicated ulcer. Within each cohort of subjects, UGIB rates for individuals currently using NSAIDs (triangles) exceed those for non-users (circles), but the effect of prior history greatly amplifies that of NSAID use (data from ref. 20).