| A randomized, double-blind, placebo-controlled study of continuous infusion methylprednisolone was performed in 20 ARDS patients. Plasma concentrations (n = 110) were determined using HPLC. Population pharmacokinetic analysis was performed using nonlinear mixed-effects models (NONMEM). A one-compartment model with time-dependent, nonlinear increase in clearance (CL) was used to describe plasma concentration data. Initial clearance (CLo) increased non-linearly to maximal (CLmax) after 7 days. Population mean estimates (+/-S.E.) of parameters were: CLo = 13.2 +/- 2.4 L/hr, CLmax = 25.0 +/- 3.6 L/hr, time of half-maximal increase in CL (T50) 41.1 +/- 8.2 hr, gamma (Hill coefficient) = 3.8 +/- 0.6, and Vd = 137 +/- 30.2 L. Evaluation of disease progression indices and patient demographics as covariates revealed no significant correlation. Means (+/-S.D.) of protein binding as determined by ultrafiltration differed between controls (72% +/- 4%) and patients (46% +/- 11%). Survival was evaluated in 17 patients. CL increased an average 127% in survivors (n = 16). CL decreased 76% in the non-survivor.;Transport experiments were conducted using LLC-PK and L-MDR1 cells. Basal (B) to apical (A) and apical to basal permeability (Peff = dC/ dt x V x 1/A x 1/Co) were compared in L-MDR1 cells to assess transport efficiency (Teff = Peff(B→A)/Peff(A→B) ). Rank order of Teff was: methylprednisolone > prednisolone > betamethasone > dexamethasone and prednisone > cortisol > cortisone (range 3.6 to 26.6). LLC-PK Teff was approximately one for all glucocorticoids. J774.2 and J774.2 mdr1b cells were chosen to investigate P-gp's effect on glucocorticoid receptor (GR) binding. Total and specific binding were reduced by mdr1b. Verapamil, a P-glycoprotein inhibitor, restored GR binding in J774.2 mdr1b cells to levels seen in J774.2 cells.;If clearance improvement relates to clinical status, it may be possible to use clearance as a pharmacodynamic response marker. Deteriorating clearance in the nonsurvivor suggested response was related to factor(s) other than methylprednisolone tissue availability (e.g., cellular penetration). P-glycoprotein transports methylprednisolone with the greatest efficiency. Therefore, the effect of P-glycoprotein on the intracellular accumulation/activity of glucocorticoids would be most pronounced with methylprednisolone. |
