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Open AccessAn Explanation of Why Dose-Corrected Area Under the Curve for Alternate Administration Routes Can Be Greater than for Intravenous Dosing
It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We tea...
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Article
Acyl-CoA thioesters as chemically-reactive intermediates of carboxylic acid-containing drugs
Several carboxylic acid-containing drugs have been withdrawn from clinical use due to adverse drug reactions including idiosyncratic hepatotoxicity and anaphylaxis. Carboxylic acid drugs are increasingly being...
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Article
Open AccessThe Uses and Advantages of Kirchhoff’s Laws vs. Differential Equations in Pharmacology, Pharmacokinetics, and (Even) Chemistry
In chemistry, rate processes are defined in terms of rate constants, with units of time−1, and are derived by differential equations from amounts. In contrast, when considering drug concentrations in biological s...
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Article
Open AccessState of the Art and Uses for the Biopharmaceutics Drug Disposition Classification System (BDDCS): New Additions, Revisions, and Citation References
The Biopharmaceutics Drug Disposition Classification system (BDDCS) is a four-class approach based on water solubility and extent of metabolism/permeability rate. Based on the BDDCS class to which a drug is as...
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Article
Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies
Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here.
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Article
Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing
Pharmacokinetic differences between manufacturing batches, well established for inhaled drug products, preclude control of patient risk in the customary two-way (single batch) pharmacokinetic bioequivalence cr...
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Article
Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans
A dataset of fraction excreted unchanged in the urine (fe) values was developed and used to evaluate the ability of preclinical animal species to predict high urinary excretion, and corresponding poor metaboli...
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Article
Open AccessThere is Only One Valid Definition of Clearance: Critical Examination of Clearance Concepts Reveals the Potential for Errors in Clinical Drug Dosing Decisions
Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engin...
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Investigating Intestinal Transporter Involvement in Rivaroxaban Disposition through Examination of Changes in Absorption
The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in rivaroxaban disposition based on in vitro studies, s...
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Article
Volume of Distribution is Unaffected by Metabolic Drug–Drug Interactions
It has been recognized that significant transporter interactions result in volume of distribution changes in addition to potential changes in clearance. For drugs that are not clinically significant transporte...
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Article
Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition
The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Reco...
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Article
Investigating the Theoretical Basis for In Vitro–In Vivo Extrapolation (IVIVE) in Predicting Drug Metabolic Clearance and Proposing Future Experimental Pathways
Extensive studies have been conducted to predict in vivo metabolic clearance from in vitro human liver metabolism parameters (i.e., in vitro–in vivo extrapolation (IVIVE)) with little success. Here, deriving IVIV...
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The Necessity of Using Changes in Absorption Time to Implicate Intestinal Transporter Involvement in Oral Drug-Drug Interactions
In drug discovery and development, it is of high interest to characterize the potential for intestinal drug-drug interactions to alter bioavailability of a victim drug. For drugs that are substrates of both in...
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Article
Challenging the Relevance of Unbound Tissue-to-Blood Partition Coefficient (Kpuu) on Prediction of Drug-Drug Interactions
To examine the theoretical/practical utility of the liver-to-blood partition coefficient (Kpuu) for predicting drug-drug interactions (DDIs), and compare the Kpuu-approach to the extended clearance concept AUCR-a...
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Article
Food, Acid Supplementation and Drug Absorption – a Complicated Gastric Mix: a Randomized Control Trial
The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastri...
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Article
How Transporters Have Changed Basic Pharmacokinetic Understanding
The emergence and continued evolution of the transporter field has caused re-evaluation and refinement of the original principles surrounding drug disposition. In this paper, we emphasize the impact that trans...
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Article
Interlaboratory Variability in Human Hepatocyte Intrinsic Clearance Values and Trends with Physicochemical Properties
To examine the interlaboratory variability in CLint values generated with human hepatocytes and determine trends in variability and clearance prediction accuracy using physicochemical and pharmacokinetic paramete...
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Article
Understanding drug–drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs
Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug–drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral syste...
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Article
The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses
To derive the theoretical basis for the extended clearance model of organ elimination following both oral and IV dosing, and critically analyze the approaches previously taken.
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Article
Why Drugs Fail in Late Stages of Development: Case Study Analyses from the Last Decade and Recommendations
New drug development is both resource and time intensive, where later clinical stages result in significant costs. We analyze recent late-stage failures to identify drugs where failures result from inadequate ...
