Zonal distribution of paracetamol glucuronidation in the isolated perfused rat liver.

1. The lobular distribution of paracetamol conjugation was studied using antegrade and retrograde perfusion of isolated rat liver. After addition of 25 mg of paracetamol, recovery of sulphate from antegrade perfusions was greater than from retrograde perfusions indicating periportal predominance of this metabolic pathway. 2. Recovery of sulphate was greater than recovery of glucuronide after addition of 25 mg of paracetamol during both antegrade and retrograde perfusions. Recovery of sulphate was similar after addition of 25 or 100 mg of paracetamol, whereas recovery of the glucuronide was increased at the higher dose, indicating a higher capacity for glucuronidation than for sulphation, but a higher affinity for sulphation. 3. Recovery of glucuronide from antegrade and retrograde perfusions was similar after addition of 25 mg of paracetamol, but was greater from antegrade perfusions after addition of 100 mg. This indicates that drug concentration may be an important determinant of the zonal distribution of drug metabolism. Factors other than localization of drug-metabolizing enzymes, such as competition with other metabolic pathways or availability of cofactors, may also influence the apparent zonal distribution of drug metabolism.