Salicylate metabolism in twins. Evidence suggesting a genetic influence and induction of salicylurate formation

Abstract

To evaluate the contribution of genetic influences on the individual variation in plateau serum salicylate levels, salicylate metabolism was studied in seven pairs of identical and six pairs of fraternal twins.Under the conditions of this study, after a single i.v. dose (40 mg/kg) of sodium salicylate, the serum salicylate concentration versus time curve approximated a straight line on linear coordinates (appeared approximately zero order). The slopes of the decay curves ranged between 0.64 and 1.02. The intrapair variation for identical twin pairs was significantly less than for fraternal twin pairs (P = 0.044). Likewise pleateau serum salicylic acid concentrations (milligrams/deciliter) and total salicylic acid excretion rate after multiple doses demonstrated significantly less intrapair variation for identical twins than for fraternal twins (P = 0.043 and 0.006). Plateau salicylurate excretion (milligram/kilogram per hour) differences after multiple dosing had a P = 0.067. Michaelis-Menton constant for salicylurate formation and hours to 50% excretion after the i.v. dose were not different when comparing identical and nonidentical twins. Salicylurate formation rates were increased after 3 days of oral therapy, and this induction phenomenon may account for much of the apparent discrepancy between genetic influences on salicylurate formation rates observed after single and multiple dose salicylate administration. This study suggests that the plateau concentration of serum salicylate varies among individuals given the same weight-adjusted dose in part because of genetically determined variations in their metabolism of salicylate.