Blood or Plasma? Which Should You Assay for Drug Concentration?

Since modern drug development, drug concentration assays have almost exclusively used plasma as a matrix rather than whole blood. Various theories about assay sensitivity, matrix interference, protein binding, and free drug movement have been put forth to explain why it is “best” to measure drug concentrations in plasma. Personally none of these theories convinces me … Continued

Why Should You Evaluate Dose Proportionality?

Dose proportionality is a common phrase used pharmacokinetics. Early in the pre-clinical development process, we evaluate dose proportionality in animal species. Then if the drug advances to clinical trials, one of the first assessments in humans is to evaluate dose proportionality. Why is it so important? What do we learn from understanding dose proportionality? What … Continued

What is the Difference Between PK and TK?

PK is the abbreviation for pharmacokinetics. TK is the abbreviation for toxicokinetics. Some consider these to be distinct specialties while others consider them to be the same. Let me explain and then I would like to see what you think. Pharmacokinetics generally deals with doses that are in a therapeutic range. Thus common dose ranges … Continued

Why are PK Parameters Lognormally Distributed?

The statistical analysis of pharmacokinetic parameters is often overlooked and not always well understood. The disconnect between the pharmacokineticist and the biostatistician can often be a huge stumbling block that prevents the appropriate analysis of PK parameters. While I cannot solve all the disagreements between pharmacokineticists and biostatisticians in a single blog post, I hope … Continued

What are Direct and Indirect Pharmacodynamic Models?

When constructing pharmacodynamic (PD) models, you will often encounter the adjectives “direct” and “indirect” describing the associated PD model. This terminology was very confusing to me when I was learning about PD modeling. Hopefully a brief explanation will help you. Let’s start with the direct PD model. In this type of model, the drug is … Continued

What is Modeling and Simulation?

I am currently attending a short conference on modeling and simulation in pediatric clinical pharmacology, and I noticed that many people in the conference don’t have a good grasp on what “Modeling and Simulation” means. I think most of them think that it is an extremely complicated mathematical concoction that is intended to keep everyone … Continued

Unexpected Effect of Rifampin on the Pharmacokinetics of Linezolid: In Silico and In Vitro Approaches to Explain Its Mechanism

The effect of rifampin on the steady-state pharmacokinetics of linezolid was evaluated in an open-label, multiple-dose, crossover study in 16 healthy subjects. When coadministered with rifampin, area under the plasma concentration-time curve over the dosing interval and maximum concentration values for linezolid were reduced approximately 32% and 21%, respectively. Time to maximum concentration and apparent … Continued

Excretion of the Principal Urinary Metabolites of Phenytoin and Absolute Oral Bioavailability Determined by Use of a Stable Isotope in Patients with Epilepsy

The anticonvulsant properties of phenytoin (PHT) were discovered in 1938. Since then, it has been one of the most widely used antiepileptic drugs. It is slowly absorbed, extensively plasma protein-bound, exhibits a nonlinear, concentration-dependent pharmacokinetic profile, and has a narrow therapeutic range. We determined PHT bioavailability during steady-state therapy by 1) measurement of the two … Continued

Three-dimensional Quantitative Structure-activity Relationship Studies on UGT1A9-mediated 3-O-glucuronidation of Natural Flavonols Using a Pharmacophore-based Comparative Molecular Field Analysis Model

Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., Km), Vmax, intrinsic clearance (CLint) = Vmax/Km] derived for flavonols. This article aims to construct position (3-OH)-specific … Continued

Identification of Curcumin Derivatives as Human Glyoxalase I Inhibitors: A Combination of Biological Evaluation, Molecular Docking, 3D-QSAR and Molecular Dynamics Simulation Studies

Several recent developments suggest that the human glyoxalase I (GLO I) is a potential target for anti-tumor drug development. In present study, a series of curcumin derivatives with high inhibitory activity against human GLO I were discovered. Inhibition constant (KI)values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600μM, 2.600μM, 3.200μM, … Continued