Salicylate Metabolism in Twins

Abstract

A B S T R A C T 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 genetiDr. Furst's present address is the

Salicylate pharmacokinetics in patients with rheumatoid arthritis.

“…Overall the pattern of increase in SU concentration during the 6 weeks paralleled the descriptions of the change in Vmax for SU formation from previous studies; i.e. Furst et al (1977) observed an increase in Vmax for SU formation within 3 days of starting salicylate therapy, Gunsberg et al (1984) suggested that the increase in Vmax was not complete within 7 days of starting therapy and Day et al (1983,1988) found that induction was maximal at 2 weeks. Our unpublished data also suggest that there is a limit to the increase.…”

“…Several authors have explained the decline in salicylate concentrations by induction of the enzymatic process responsible for the formation of salicylurate (Day et al, 1983(Day et al, , 1988Furst et al, 1977;Rumble et al, 1980). Consistent with this theory there was a significant increase in both total and unbound Vmax for salicylurate formation.…”

“…In the absence of other explanations, the decrease in plasma salicylate concentrations has been attributed to induction of the formation of salicyluric acid. Furst et al (1977) observed a significant increase in the Vmax for salicylurate formation from 0.92 mg kg-1 h-1 to 1.36 mg kg-' h-1, after only 3 days of oral aspirin therapy in 26 healthy subjects, while Rumble et al (1980) observed a nonsignificant increase in the urinary output of salicylurate during chronic dosing. Day et al (1983Day et al ( , 1988 suggested that the induction process was time-limited, with no further increase in Vmax after 2 weeks.…”

“…Plasma salicylate concentrations above 150 ,ug/mL are said to be necessary to obtain a significant anti-inflammatory response (KochWeser, 1972) and, although oral aspirin doses greater than 3900 mg/day will generally result in an adequate concentration, genetic factors (Furst et al, 1977) and the complexity of the pharmacokinetics often make it difficult to achieve this therapeutic plasma concentration. This seems particularly true of patients with rheumatoid arthritis (Graham et al, 1977;Gunsberg et al, 1984).…”

Determinants of Aspirin Metabolism in Healthy Men and Women: Effects of Dietary Inducers of UDP-Glucuronosyltransferases

“…Although numerous studies have reported differences in drug metabolism among ethnic groups [29], few studies have looked at the effects of ethnicity on ASA metabolism specifically. Williams et al [30] reported significantly lower plasma esterase activity (hydrolysis of ASA to SA) in individuals from Ghana compared to individuals living in the UK.…”