Hepatic structure‐pharmacokinetic relationships: The hepatic disposition and metabolite kinetics of a homologous series of O‐acyl derivatives of salicylic acid

Abstract

1 The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-situ rat liver preparation. 2 The hepatic venous out¯ow pro®les for the parent esters 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 variance (CV 2 ) for the parent esters and generated SA. 3 Pregenerated SA ([ 14 C]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4 The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5 The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no signi®cant 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 AUC', MTT and CV 2 for the parent ester and metabolite. The moments values obtained using the twocompartment dispersion model show similar trends to the corresponding moments values obtained from the out¯ow pro®les using a non-parametric approach. 7 The more lipophilic aspirin analogues are more con®ned to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet e ects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.

Hepatic Disposition and Metabolite Kinetics of a Homologous Series of Diflunisal Esters

“…We have found a similar result for salicylate esters. 3 These results are in contrast with the increase in barbiturate MTT with carbon chain length as reported by Chou et al 1 It is important to recognize that, unlike diflunisal and salicylate esters, barbiturates are poorly metabolized so that CL int = 0 and a = 1. Accordingly, with protein free perfusate, eq 20 reduces to Hence, a decrease in f uc with lipophilicity results in an increased MTT with lipophilicity as reported.…”

“…Hung et al used a similar method to investigate the hepatic distribution and metabolite kinetics for a homologous series of O-acyl esters of salicylate. 3 This work showed that the hepatic availability (AUC′) of these salicylic acid esters decreased with increasing carbon chain length in the O-acyl moiety. In the present paper, we compared the hepatic disposition of a homologous series of diflunisal esters using a similar method.…”

“…1,2 In a recent paper, we presented studies on the disposition of a homologous series of O-acyl derivatives of salicylic acid in the perfused rat liver. 3 Diflunisal, 5-(2,4-difluorophenyl) salicylic acid, is a long acting nonsteroidal antiinflammatory drug. It is a lipophilic analogue of salicylic acid.…”

Commentary: Using the Convection–Dispersion Model and Transit Time Density Functions in the Analysis of Organ Distribution Kinetics

“…In practice, impulse injections in perfused liver preparations are given as an input into flowing perfusate and have been described as "injection in fluid flux". 9 Also in practice, and outflow concentration is usually measured as a mean concentra-tion in the outflow perfusate collected by a fraction collector [12][13][14] and is therefore also a flux concentration C F . Importantly, C P can be related to C F through the mass conservation law by noting that the total mass flux equals the sum of the convective and dispersive fluxes and that: 9…”

Characterization of the Physiological Spaces and Distribution of Tolbutamide in the Perfused Rat Pancreas

“…Most studies have examined antibiotic distribution in patients suffering pancreatitis (for review see (1)), with the limited work undertaken on the physiological pharmacokinetics in this organ being limited to in vivo partitioning studies (2Y4) and the transport of amino acids (5Y12). First-pass multiple indicator dilution perfusion models have been utilised to examine the efflux kinetics of numerous solutes in other organs including the liver (13), heart (14), lung (14), kidney (14), hindlimb (15) and head (16). However, to our knowledge, no published studies have yet examined the disposition kinetics of drugs in the perfused pancreas using a multiple indicator dilution technique.…”