ABSTRACT
The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.
Subject(s)
Cardiovascular Agents/metabolism , Digoxin/metabolism , Membrane Transport Proteins/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Biological Transport , Cardiovascular Agents/adverse effects , Cardiovascular Agents/pharmacokinetics , Digoxin/adverse effects , Digoxin/pharmacokinetics , Drug Interactions , Humans , Membrane Transport Proteins/metabolism , Models, Biological , Patient Safety , Risk Assessment , Risk FactorsABSTRACT
Drug interactions due to efflux transport inhibition at the blood-brain barrier (BBB) have been receiving increasing scrutiny because of the theoretical possibility of adverse central nervous system (CNS) effects identified in preclinical studies. In this review, evidence from pharmacokinetic, pharmacodynamic, imaging, pharmacogenetic, and pharmacovigilance studies, along with drug safety reports, is presented supporting a low probability of modulating transporters at the human BBB by currently marketed drugs.
Subject(s)
Blood-Brain Barrier/metabolism , Drug Interactions , Membrane Transport Proteins/metabolism , Pharmaceutical Preparations , Biological Transport/physiology , Drug Design , Drug Evaluation, Preclinical , Humans , PharmacokineticsABSTRACT
This white paper provides a critical analysis of methods for estimating transporter kinetics and recommendations on proper parameter calculation in various experimental systems. Rational interpretation of transporter-knockout animal findings and application of static and dynamic physiologically based modeling approaches for prediction of human transporter-mediated pharmacokinetics and drug-drug interactions (DDIs) are presented. The objective is to provide appropriate guidance for the use of in vitro, in vivo, and modeling tools in translational transporter science.
Subject(s)
Drug Interactions , Membrane Transport Proteins/metabolism , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Animals , Biological Availability , Biological Transport/drug effects , Brain/metabolism , Guidelines as Topic , Humans , Kidney/metabolism , Liver/metabolism , Models, Biological , Tissue DistributionABSTRACT
The influence of microsomal concentration on unbound fraction (fu(mic)), half-life (t(1/2)), apparent intrinsic clearance (CL(int,app)) and apparent Michaelis-Menten constant (K(m,app)) was examined for two compounds, one representative of high nonspecific binding to microsomes (compound A) and one representative of low (compound B). Kinetic parameters were estimated for the two probe compounds at two human microsomal protein concentrations (0.46 and 2.3 mg/ml) and cytochrome P450 concentrations (0.20 and 1.0 microM), representing a 5-fold difference in microsomal concentration. For compound A, fu(mic) and CL(int,app) were inversely proportional to microsomal concentration. Conversely, the K(m,app) of compound A was proportional to microsomal concentration and the half-life was unchanged. For compound B, half-life was inversely proportional to microsomal concentration. In this case, fu(mic), CL(int,app), and K(m,app) were not proportionally influenced. The experimental observations were entirely consistent with that predicted by a mathematical relationship between microsomal concentration, fu(mic), t(1/2), CL(int,app), and K(m,app). These results demonstrate that when nonspecific binding is extensive, CL(int,app) is dependent on the arbitrary choice of microsomal concentration included in the incubation.
Subject(s)
Microsomes/metabolism , Models, Biological , Pharmacokinetics , Drug Stability , Half-Life , Metabolic Clearance RateABSTRACT
Previously, we have hypothesized a causal relationship between some measures of immunosenescence and the age-related decline in sympathetic noradrenergic (NA) nerve fibers in spleen and lymph nodes of F344 rats. In the present study, we investigated this interrelationship further by measuring NK cell activity, Con A-induced IL-2 production, norepinephrine (NE) concentration, and morphological localization of NA and neuropeptide-Y (NPY) nerve fibers in the spleens of old (21 months old) male F344 rats after 10 weeks of daily treatment with low doses of L-deprenyl, an irreversible monoamine oxidase-B inhibitor, followed by a 9-day wash-out period. NK cell activity and Con A-induced IL-2 production were increased in deprenyl-treated old rats in comparison to untreated and saline-treated old rats. Deprenyl treatment did not alter the percentage of CD5+ T-cells, but moderately increased the percentage of sIgM+ B-cells in the spleens of old rats. In addition to changes in immune responses, NE content and the volume density of NA and NPY nerve fibers were partially augmented in the spleens of deprenyl-treated old rats. In a separate study, various concentrations of deprenyl were added in vitro to spleen cells from young and old F344 rats to examine the direct effects of the drug on Con A-induced IL-2 production. In contrast to in vivo treatment, in vitro addition of deprenyl did not alter the Con A-induced IL-2 production by splenocytes from old rats. Together, these results suggest that the ability of deprenyl to enhance certain immune responses are interlinked to the restoration of sympathetic NA and NPY nerve fibers in the spleens of old rats.
