The Effect of Protein Binding on the Hepatic First Pass of O-Acyl Salicylate Derivatives in the Rat

Abstract

In this work the in-situ perfused rat liver has been used to examine the effect of changing the protein content of the perfusate on the hepatic extraction of O-acyl esters of salicylic acid. The hepatic availability (F) of these solutes was studied at a flow-rate of 30 mL min(-1) with perfusate albumin concentrations of 0, 2, and 4% w/v. The hepatic availability of the esters was shown to decrease with increasing carbon-chain length in the O-acyl group; for all the esters the hepatic availability increased with increasing albumin concentration in the perfusate. The dispersion-model-derived efficiency number (RN) of the esters was shown to increase with increasing lipophilicity and decrease with increasing albumin concentration in the perfusate. The unbound fraction (fu) of the esters decreased with lipophilicity. RN/fu for acetylsalicylic acid remained relatively constant as the albumin concentration was increased. However, RN/fu for n-pentanoyl- and n-hexanoylsalicylic acids increased significantly as albumin concentration increased from 0% to 4%. Thus, for the more lipophilic solutes (n-pentanoyl- and n-hexanoylsalicylic acids) the presence of albumin apparently facilitates the uptake of unbound solute relative to acetylsalicylic acid.

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

“…Outlet samples were collected via a fraction collector over 1 min. The outlet samples were assayed for [ 14 C]‐salicylic acid (scintillation counting), O‐acyl ester and metabolite SA (high performance liquid chromatography, HPLC analysis) (Hung et al , 1998).…”

“…The O-acyl derivatives of salicylic acid (Figure 1) were prepared by esteri®cation of salicylic acid with the appropriate acyl-anhydride as described elsewhere (Hung et al, 1997). The single-pass in situ rat liver perfusion preparation used in this study is described in detail previously (Cheung et al, 1996) (Hung et al, 1998). Injections of C4SA and C5SA were performed in each of four liver preparations.…”

Prediction of human pharmacokinetics—gut-wall metabolism

“…Despite a considerably longer residence time in the intestines compared with the liver (hours vs seconds), the uptake capacity of the intestines appear to be somewhat lower than that of the liver. For example, enalaprilat and atenolol have low and moderate GI f a (0.1 and 0.5, respectively) Chiou & Barve 1998), and their hepatic uptake CL (in rats; human data are not available) is estimated to be 20% of hepatic blood flow rate (Q H ) and > Q H , respectively (Schwab et al 1990;Hung et al 1997). Available human in-vivo small intestinal P e data obtained during Loc-I-Gut perfusion experiments (lumen-to-blood direction; 10-cm intestinal segment length), and small intestinal transit time (3 h) and length (7 m) enable an estimation of the small intestinal uptake CL of various compounds (Davies & Morris 1993;Fagerholm et al 1996).…”

Drug structure–transport relationships

“…The lack of solute dependency on size contrasts with transport of solutes through skin where solute size is dominating [42]. Other studies include protein binding [107], interspecies scaling [108], liver regeneration [109], metabolite kinetics [110, 111], binding, ion trapping and disease [112–117]. In addition, we have examined saturable uptake of digoxin and its inhibition by rifampicin [118].…”