On the Volume of Distribution at Steady State and Its Relationship With Two‐Compartmental Models

Yates, James; Arundel, Philip A.

doi:10.1002/jps.21089

Cited by 25 publications

(12 citation statements)

References 29 publications

(45 reference statements)

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“…The typical compartmental model assumes the liver and kidneys are part of the central compartment, as they are highly perfused organs and assumed to be in rapid equilibrium with the plasma, thus providing for central compartment elimination. However, when elimination does not occur from the central compartment, these three measures will significantly under-predict distribution volume (6,7). Therefore, it may be important to consider a possible case where transporter dysfunction means the liver or kidneys are not in rapid equilibrium with the plasma, such that elimination occurs from a peripheral compartment.…”

Section: Introductionmentioning

confidence: 99%

Effects of Drug Transporters on Volume of Distribution

Grover

Benet

2009

AAPS J

125

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Abstract. Recently, drug transporters have emerged as significant modifiers of a patient's pharmacokinetics. In cases where the functioning of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout animals, the resulting change in volume of distribution can lead to a significant change in drug effect or likelihood of toxicity, as well as a change in half life independent of a change in clearance. Here, we review pharmacokinetic interactions at the transporter level that have been investigated in animals and humans and reported in literature, with a focus on the changes in distribution volume. We pay particular attention to the differing effects of changes in transporter function on the three measures of volume. Further, trends are discussed as they may be used to predict volume changes given the function of a transporter and the primary location of the interaction. Because the liver and kidneys express the greatest level and variety of transporters, we denote these organs as the primary location of transporter-based interactions. We conclude that the liver is a larger contributor to distribution volume than the kidneys, in consideration of both uptake and efflux transporters. Further, while altered distribution due to secondary interactions at tissues other than the liver and kidneys may have a pharmacodynamic effect, these interactions, at least at the blood-brain barrier, do not appear to significantly influence overall distribution volume. The analysis provides a framework for understanding potential pharmacokinetic interactions rooted in drug transporters as they modify drug distribution.

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Section: Introductionmentioning

confidence: 99%

Effects of Drug Transporters on Volume of Distribution

Grover

Benet

2009

AAPS J

125

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“…This is an obvious limitation of the study, because additional data would provide a more detailed picture of RES disposition. In addition, single-dose plasma data collected here did not aid in discerning elimination from the central versus peripheral compartment (Berezhkovskiy, 2004;Yates and Arundel, 2008). Thus, a criticism of the models presented is the assumption of elimination solely from the central compartment.…”

Section: Sharan Et Almentioning

confidence: 81%

In Vivo-Formed versus Preformed Metabolite Kinetics of trans-Resveratrol-3-sulfate and trans-Resveratrol-3-glucuronide

et al. 2012

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ABSTRACT:Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.

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“…It can be shown [25] that there is a relationship between the parameterisation of the two models that ensures that they behave identically with respect to the observation: Table 2 produce the same observed concentration-time profile.…”

Section: Two Compartment Models With Different Routes Of Elimination mentioning

confidence: 87%

“…There are four simultaneous equations (5a -d) for five unknown parameters; therefore, the model is unidentifiable. It may be shown [25] that the identifiable combinations are:…”

Section: Two Compartment Model With Two Routes Of Eliminationmentioning

confidence: 99%

Structural identifiability and indistinguishability of compartmental models

Walker

et al. 2009

Expert Opinion on Drug Metabolism & Toxicology

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The deterministic identifiability of models is only normally considered if a problem becomes apparent in the parameter identification stage of data analysis. If no problem is perceived then the analysis will continue. However, although the problem does not become apparent, the implications of ambiguities in what is inferred from the data should be considered. This paper reviews some fundamentals with respect to model indistinguishability and parameter identifiability.

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On the Volume of Distribution at Steady State and Its Relationship With Two‐Compartmental Models

Cited by 25 publications

References 29 publications

Effects of Drug Transporters on Volume of Distribution

Effects of Drug Transporters on Volume of Distribution

In Vivo-Formed versus Preformed Metabolite Kinetics of trans-Resveratrol-3-sulfate and trans-Resveratrol-3-glucuronide

Structural identifiability and indistinguishability of compartmental models

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