Comparative bioavailability: A new type of in vitro-in vivo correlation exemplified by prednisone

The average time to reach half-maximal plasma concentration of prednisolone and the average plasma concentrations of prednisolone at 0.5 and 1 hr obtained from three crossover bioavailability studies, involving testing of commercially available 5-mg prednisone tablets, were highly correlated (r⪖ 0.88) with parameters derived from in vitro tablet dissolution rates performed in the spin filter apparatus of Shah. The in vitro parameters were the times to dissolve 16% or 50% of the labeled amount of prednisone or the percent of the labeled amount of prednisone dissolved in 20 min in water at 37‡C. Such correlations may be useful in the setting of in vitro dissolution rate specifications for commencal prednisone tablets .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45065/1/10928_2005_Article_BF01086152.pd

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

Modeling allosteric signal propagation using protein structure networks

Allosteric communication in proteins can be induced by the binding of effective ligands, mutations or covalent modifications that regulate a site distant from the perturbed region. To understand allosteric regulation, it is important to identify the remote sites that are affected by the perturbation-induced signals and how these allosteric perturbations are transmitted within the protein structure. In this study, by constructing a protein structure network and modeling signal transmission with a Markov random walk, we developed a method to estimate the signal propagation and the resulting effects. In our model, the global perturbation effects from a particular signal initiation site were estimated by calculating the expected visiting time (EVT), which describes the signal-induced effects caused by signal transmission through all possible routes. We hypothesized that the residues with high EVT values play important roles in allosteric signaling. We applied our model to two protein structures as examples, and verified the validity of our model using various types of experimental data. We also found that the hot spots in protein binding interfaces have significantly high EVT values, which suggests that they play roles in mediating signal communication between protein domains

Comparative bioavailability: Eight commercial prednisone tablets

Two four-treatment crossover bioavailability studies were performed in panels of 12 adult male volunteers with eight different commercial prednisone tablets. Plasma samples from the first study were assayed by radioimmunoassay for both prednisone and prednisolone. Plasma samples from the second study were assayed for prednisolone only. Statistical analyses of the data showed significant differences in the rate of appearance of prednisolone in plasma, but not in the amount convened to prednisolone. Some observations are made on the relationships between prednisone and prednisolone concentrations in plasma following oral administration of prednisone .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45064/1/10928_2005_Article_BF01086151.pd

Bioavailability of prednisolone tablets

Two fourtreatment crossover studies were performed using 12 adult male volunteers in each with seven different commercially available prednisolone tablets. Plasma samples were assayed for prednisolone by a radioimmunoassay method. Statisacal analyses of the data, by analysis of variance for crossover design (ANOVA), showed no significant differences among the treatment averages at any of the sampling times except at 0.25 and 4 hr in one of the studies. There were also no significant differences among the treatment averages for peak plasma level, time of peak plasma level, area 0–12 hr, area 0–24 hr, and the halflife of elimination of prednisolone. We conclude that the average plasma concentrations of prednisolone are superimposable in a statistical sense and that the tablets tested are bioequivalent. Results of dissolution studies of six tablets of each of the seven lots of prednisolone tablets, using deaerated water in the spin filter apparatus, are presented.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45072/1/10928_2005_Article_BF01065399.pd

Evidence of nonlinearity in digoxin pharmacokinetics

Six normal male volunteers received 0.5 mg label doses of digoxin as (a) a bolus intravenous injection over 2 min, (b) a constant rate intravenous infusion over 1 hr, (c) a constant rate intravenous infusion over 3 hr, and (d) a solution in 5% dextrose given orally. Plasma concentrations of digoxin were measured by radioimmunoassay for a 4 day period and urinary excretion for a 6 day period after the single doses. The mean (coefficient of variation) total areas under the plasma concentration-time curves per 0.5 mg of digoxin were (a) 35.55 (14.8%), (b) 30.20 (27.7%), (c) 25.80 (35.5%), and (d) 15.47 (49.9%); the means differed significantly (0.01>p>0.005). The mean (coefficient of variation) total amounts excreted in the urine as a fraction of the dose were (a) 0.689 (6.31%), (b) 0.517 (20.4%), (c) 0.588 (16.8%), and (d) 0.374 (23.4%); the means differed significantly (p<0.001. Both the total clearance and the nonrenal clearance of digoxin differed significantly with the method of intravenous administration. The slower the rate of input of digoxin to the body, the greater were both the total clearance and the nonrenal clearance of the drug, which strongly suggests nonlinear pharmacokinetics .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45078/1/10928_2005_Article_BF01068079.pd