HEPATIC STRUCTURE-PHARMACOKINETIC RELATIONSHIPS - THE HEPATIC DISPOSITION AND METABOLITE KINETICS OF A HOMOLOGOUS SERIES OF O-ACYL DERIVATIVES OF SALICYLIC-ACID

1 The hepatic disposition and metabolite kinetics of a homologous seri es of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and oct anoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA , respectively) was determined using a single-pass, in-sills rat liver preparation. 2 The hepatic venous outflow profiles for the parent est ers and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized varianc e (CV2) for the parent esters and generated SA. 3 Pregenerated SA ([C- 14]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4 The overall recovery of eater plus metabolite was 89% of the ester dose injected and indep endent of the eater carbon number, suggesting that ester extraction wa s due to hepatic metabolism to salicylic acid. 5 The metabolite AUC' v alue increased directly with the lipophilicity of the parent ester (fr om 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decre ased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophi licity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA) . However, the parent MTT value shows no significant change across the series. 6 The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA . Consequently, these parameters were used to estimate the values of A UG', MITT and CV2 for the parent ester and metabolite. The moments val ues obtained using the two-compartment dispersion model show similar t rends to the corresponding moments values obtained from the outflow pr ofiles using a non-parametric approach. 7 The more lipophilic aspirin analogues are more confined to the portal circulation after oral admin istration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selec tivity as an anti-thrombotic agent has been postulated to be due to se lective anti-platelet effects in the portal circulation, the more lipo philic and highly extracted analogues are potentially more selective a nti-thrombotic agents than aspirin.