Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination

Berezhkovskiy, Leonid M.

doi:10.1002/jps.20073

Cited by 296Pharmacogenetics and Drug MetabolismPharmaceutical studies and practicesAntibiotics Pharmacokinetics and Efficacy

Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination

Berezhkovskiy, Leonid M.·2004·Journal of Pharmaceutical Sciences

DOI 10.1002/jps.20073

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Abstract

The problem of finding the steady-state volume of distribution V(ss) for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation V(ss) = (D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, V(ss) = (D/AUC)*MRT(int), was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRT(int) is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRT(int) cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRT(int) becomes equal to MRT = AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, V(ss) = (D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRT(int), as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue-plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated V(ss) = (D/AUC)*MRT and the true value given by (D/AUC)*MRT(int) is discussed.

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The Kp values for each tissue can be calculated by three mechanistic models.
“The K p values for each tissue can be calculated by three mechanistic models (Table 2). 42 , 43 , 44”
From Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction (2022) · cites this paper as [42]
Alternative models have been developed to account for overprediction in Vss for highly lipophilic compounds.
“Alternative models have been developed to account for the overprediction in V ss for highly lipophilic compounds”
From IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes (2017) · cites this paper as Berezhkovskiy, 2004

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Authors: Berezhkovskiy, L. M.
Corresponding author: Berezhkovskiy, Leonid M.
Venue: Journal of Pharmaceutical Sciences
Publisher: Elsevier BV
Published: 2004-06
Volume: 93
Issue: 6
Pages: 1628-1640
ISSN: 0022-3549 (ISSN-L)
DOI: 10.1002/jps.20073
OpenAlex: W1983118095
Cited by: 296
References: 14
Citations by year: 2026: 18 · 2025: 22 · 2024: 22 · 2023: 30 · 2022: 31 · 2021: 20 · 2020: 17 · 2019: 11 · 2018: 11 · 2017: 12 · 2016: 14 · 2015: 11 · 2014: 3 · 2013: 12 · 2012: 13
FWCI: 2.06
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Pharmaceutical Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords: protein binding, intravenous bolus, plasma drug concentration
MeSH terms: Pharmacokinetics, Linear Models

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Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination

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