Pharmacokinetics of steroidal muscle relaxants in isolated perfused rat liver.
Both in humans and animals hepatic elimination is an important factor determining the duration of action of non-depolarizing neuromuscular blocking drugs. To elucidate the hepato-biliary disposition of muscle relaxants the pharmacokinetics of several structurally related but physicochemically distinct steroidal neuromuscular blocking drugs were studied in isolated perfused rat livers. Pharmacokinetics analysis with the DIFFIT computer program enabled the simultaneous fitting of independently measured perfusate disappearance and biliary excretion rate curves using a numerical approach. The hepatic disposition of the steroidal muscle relaxants could be adequately described by a three compartment model with elimination from the peripheral compartment V2 (biliary excretion) and storage in a deep compartment (V3) connected to V2. In addition, for vecuronium only slow ester hydrolysis occurring in V2 and V3 was included in the model. The lipophilicity rather than the relative mobility of the muscle relaxants showed a positive relationship with biliary clearance (Cl20) and the initial hepatic uptake (Cl12), indicating that hepato-biliary transport of these organic cations is highly dependent on the hydrophobic character of the compounds. In addition, net hepatic uptake of the steroidal cations was influenced markedly by transport from the liver to perfusate (hepatic efflux). This hepatic efflux (k21) decreased with increasing lipophilicity. In contrast, the extent of intracellular sequestration into deep compartments, indicated by high k23/k32 ratios, seemed to be inversely related to the lipophilicity of the muscle relaxants and might explain the observed prolonged hepatic storage of some of these compounds. In combination with data from subfractionation studies the results indicate that the pharmacokinetic analysis of the hepatic disposition of steroidal muscle relaxants may be used to evaluate actual transport phenomena participating in the hepatic disposition of these drugs.
Department of Pharmacology and Therapeutics, University of Groningen, The Netherlands.
W E
WE
Mol
F
F
Rombout
J E
JE
Paanakker
R
R
Oosting
A H
AH
Scaf
D K
DK
Meijer
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009466:Neuromuscular Blocking Agents / Q000493:pharmacokinetics*; D010197:Pancuronium / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014673:Vecuronium Bromide / Q000031:analogs & derivatives / Q000493:pharmacokinetics
D009466:Neuromuscular Blocking Agents; C011142:Org 6368; C047940:3-deacetylvecuronium; D014673:Vecuronium Bromide; D010197:Pancuronium