METHYLPREDNISOLONE ACHIEVES GREATER CONCENTRATIONS IN THE LUNG THAN PREDNISOLONE - A PHARMACOKINETIC ANALYSIS

Previous studies in humans and rabbits demonstrated that methylprednisolone appears in the lung in greater concentration than prednisolone. To ascertain which pharmacokinetic properties of these drugs explain this difference, we gave methylprednisolone and prednisolone, 5 mg/kg intravenous bolus, to 23 adult rabbits. To measure the plasma concentration versus time curves for methylprednisolone and prednisolone, samples were obtained predose through 480 min postdose. To measure the bronchoalveolar lavage glucocorticoid concentration versus time curves, lavage was performed once per experiment at seven separate time points from 5 to 480 min postdose (two to four experiments per time point). Bronchoalveolar lavage fluid (BALF) recovery ranged from 50 to 75% and was similar in both groups. Glucocorticoid concentration in plasma and BALF was determined by high performance liquid chromatography. To normalize for the dilutional effects of lavage, epithelial lining fluid (ELF) recovery was quantitated from BALF volume and BALF and plasma urea concentrations. Pharmacokinetic parameters of the two glucocorticoids were calculated both noncompartmentally and by a three-compartment model. The extrapolated plasma glucocorticoid concentrations at time zero of methylprednisolone and prednisolone are similar, but the volume of distribution and plasma half-life of methylprednisolone are significantly greater than those of prednisolone (p < 0.05). Although the clearance of the two drugs are not significantly different, methylprednisolone appears to have a slower Cl than prednisolone. The mean residence time (the average time drug remained in body) was significantly longer for methylprednisolone than for prednisolone (p < 0.05), and plasma glucocorticoid concentrations became significantly different in the two groups by 90 min (p < 0.05). Methylprednisolone and prednisolone were rapidly distributed to the lung with similar peak ELF concentration at 5 min after bolus infusion. Linear regression equations of ELF glucocorticoid concentrations versus time demonstrate that the ELF methylprednisolone concentration is significantly greater (p < 0.05) than the ELF prednisolone concentration at time points beyond 147 min after the bolus infusion. The ratio of the uptake to efflux clearances between plasma and ELF indicates a greater tendency for methylprednisolone to locate in the ELF than for prednisolone. The three-compartment model predicts that the ELF/plasma concentration ratio will be 3.6 for methylprednisolone versus 1.7 for prednisolone. Thus, at equal plasma glucocorticoid concentrations, methylprednisolone concentrations will be approximately twice as high as prednisolone concentrations. The difference in methylprednisolone and prednisolone concentration detected in the lung is not caused by differences in the rate of distribution, but is a reflection of the larger V(d) and the longer t1/2 and MRT of methylprednisolone, as well as the greater tendency for methylprednisolone to be retained in the ELF.