Influence of Pentobarbitone on In-vivo Local Disposition of Diclofenac in Rat Liver

Abstract

Abstract Because the liver is the main organ eliminating many drugs from the body and because pentobarbitone and other analogues can inhibit biliary secretion, the influence of pentobarbitone on hepatic local disposition of diclofenac has been investigated. Diclofenac was infused into the portal and femoral veins of non-anaesthetized rats (group A) and rats anaesthetized with pentobarbitone (group B) and the plasma concentration of diclofenac and the total amount of diclofenac excreted in the bile (in both cases intact diclofenac plus its glucuronide) were simultaneously monitored by HPLC at appropriate time intervals. The time-courses of plasma concentration and amount excreted in the bile were evaluated by moment analysis with trapezoidal integration. The hepatic recovery ratio (FH) was calculated by comparing the area under the curve (AUC) of plasma concentration after intravenous infusion with that after intraportal infusion. The mean biliary transit time (tb) was estimated by subtracting the mean residence time (MRT) of the plasma data from the mean biliary residence time (MRTb) of the biliary excretion data. The FH values of diclofenac were 0.664 in group A and 0.643 in group B. The biliary excretion ratio (Fb) of total diclofenac after intravenous administration was 27.0% in group A and 14.1% in group B. The t̄b values for total diclofenac were estimated to be 0.192 h (intravenous) and 0.159 h (intraportal) in group A, and 0.174 h and 0.238 in group B. Analysis of variance showed that differences among these four t̄b values were insignificant at the 5% level. The differences in the mean residence time (MRT), total clearance (CL) and distribution volume at steady state (VSS) were insignificant between groups A and B. Whereas total and the hepatic clearance of diclofenac were not affected by pentobarbitone, biliary clearance was extensively reduced. It took a relatively long time for diclofenac to move from the sinusoid into the bile and the time was not affected by pentobarbitone.