The influence of alpha 1-acid glycoprotein on quinine and quinidine disposition in the rat isolated perfused liver preparation.
We have studied the effect of 0.5 and 2.0 g L-1 of alpha 1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2.0 g L-1) resulted in a significant decrease in clearance [quinine study (control: 9.6 +/- 2.9 vs test: 3.1 +/- 1.2 mL min-1); quinidine study (control: 9.8 +/- 2.4 vs test: 3.5 +/- 1.1 mL min-1]) and volume of distribution [quinine study (control: 1198 +/- 416 vs test: 466 +/- 95 mL); quinidine study (control: 1352 +/- 459 vs test: 317 +/- 24 mL]) but not the elimination half-life compared with control. At the lower concentration (0.5 g L-1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0.5 to 2.0 g L-1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0.5 g L-1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.
Mansor
S M
SM
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Ward
S A
SA
Edwards
G
G
Hoaksey
P E
PE
Breckenridge
A M
AM
D000818:Animals; D006207:Half-Life; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009961:Orosomucoid / Q000502:physiology*; D010101:Oxygen Consumption; D011485:Protein Binding / Q000187:drug effects; D011802:Quinidine / Q000493:pharmacokinetics*; D011803:Quinine / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D009961:Orosomucoid; D011803:Quinine; D011802:Quinidine