The pharmacokinetics of benzo[ a]pyrene in the isolated perfused rabbit lung: The influence of benzo[ a]pyrene, n-dodecane, particulate, or sulfur dioxide

Abstract

The pharmacokinetics of benzo[ a]pyrene (BaP) in the isolated perfused rabbit lung (IPL) following pretreatment of the whole animal or simultaneous administration to the IPL with n-dodecane, ferric oxide, crude airborne particulate (CAP), fly ash or sulfur dioxide have been investigated using a one compartment model. The rate constant for the appearance ( k a ) of BaP in the blood, the clearance of BaP from the blood, and the rate of appearance of BaP metabolites (RAM) were the kinetic parameters determined. BaP entered the blood rapidly with an average half-life of 11 min in experiments in which the IPLs received only BaP on perfusion. The logarithms of the clearances from these experiments were linearly correlated with the RAMs. In these experiments, pretreatment of the whole animal with BaP produced a 48–55-fold increase in BaP clearance while pretreatment with n-dodecane increased the clearance 4-fold in comparison with no pretreatment. Pretreatment with ferric oxide or ferric oxide and BaP increased the clearance by factors of 5.5 and 1.5, respectively, over those of unpretreated and BaP pretreated experiments. When BaP adsorbed on either ferric oxide, CAP or fly ash were introduced to the IPLs there was a decrease in the k a s and a large increase in the values for clearance over those estimated from the corresponding RAMs. The decrease in k a was probably the result of altered bioavailability of BaP adsorbed to the particulate, such that the effective dose was less than the administered dose. When particulate matter was introduced, the IPLs could no longer be treated as a simple one-compartment model, but the clearance from such experiments could be estimated from the RAMs. Sulfur dioxide decreased k a and increased the clearance and RAM compared to the unpretreated experiment. Introduction of CAP along with sulfur dioxide cancelled the effect that sulfur dioxide had on BaP clearance. These results suggest that the IPL represents a good system for the complex interactions of BaP with other environmental pollutants in the lung, such as sulphur dioxide, ferric oxide, and n-dodecane under a variety of experimental conditions. Data further indicate that coadministration of particulate with BaP in the lung alters the bioavailability of BaP such that more complicated pharmacokinetic models will be needed to fully explain these interactions.