Clearance Concepts: Fundamentals and Application to Pharmacokinetic Behavior of Drugs
Bibliographic record
Abstract
Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic behavior of drugs. These concepts are based on the relationship between organ extraction ratio or clearance and physiologic parameters such as the organ blood flow and the intrinsic capability of the eliminating organ to remove the free (unbound) drug from the body. Several theoretical models have been developed, which define these relationships and may be used to predict the effects of changes in the physiological parameters on various pharmacokinetic parameters of drugs, such as drug clearance. In this communication, the fundamentals of the two most widely used models of hepatic metabolism, namely the well-stirred (venous equilibrium) and parallel-tube (sinusoidal perfusion) models, are reviewed. Additionally, the assumptions inherent to these models and the differences between them in terms of their predictive behavior are discussed. The effects of changes in the physiologic determinants of clearance on the blood concentration-time profiles of drugs with low and high extraction ratio are also presented using numerical examples. Lastly, interesting and unusual examples from the literature are provided where these concepts have been applied beyond their widely known applications. These examples include estimation of the oral bioavailability of drugs in the absence of otherwise needed intravenous data, differentiation between the role of liver and gut in the first-pass loss of drugs, and distinction between the incomplete absorption and first-pass metabolism in the gastrointestinal tract after the oral administration of drugs. It is concluded that the clearance concepts are a powerful tool in explaining the pharmacokinetics of drugs and predicting the changes in their blood concentration-time courses when the underlying physiologic parameters are altered due to age, disease states, or drug interactions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.004 | 0.005 |
| Open science | 0.003 | 0.002 |
| Research integrity | 0.004 | 0.005 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".