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The Pharmacokinetics of the Weakly Protein-Bound Anionic Compound Diatrizoate in Serum and Synovial Fluid of the Horse

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Abstract

Purpose

To establish a pharmacokinetic model for the model drug, sodium diatrizoate (DTZ), allowing joint disappearance kinetics to be estimated from serum appearance kinetics following intra-articular administration, and to calculate the relative joint exposure after intravenous and intra-articular DTZ administration (Fiv/IA).

Methods

Each of five horses received an aqueous solution of 3.9 mg/kg sodium diatrizoate both intravenously and intra-articularly separated by a one-week wash out period. Serum and synovial samples were collected over 7 h and analyzed for content of model compound using inductively coupled plasma mass spectrometry.

Results

Differential equations were used for describing the transport of DTZ between the joint and the central compartment. The three-compartment lag-time model obtained demonstrates that the rate of drug appearance in the systemic circulation equals the rate of disappearance from the joint compartment. Following intravenous and intra-articular administration, an average Fiv/IA of 0.04% (n = 4) was calculated based on the synovial fluid profiles of DTZ.

Conclusions

This study implies that aspects of the intra-articular fate of DTZ can be obtained from serum data in case synovial fluid samplings are limited, for various possible reasons. The low Fiv/IA may stimulate future research in the field of intra-articular administration of anti-osteoarthritic drugs.

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Abbreviations

AIC:

Akaike information criterion

AUC:

Area under the curve

C0 :

Concentration at time zero

Cmax :

Maximum concentration

DMOAD:

Disease modifying osteoarthritic drug

DTZ:

Sodium diatrizoate

Fiv/IA :

The relative joint exposure after iv and IA drug administration

IA:

Intra-articular

ICP-MS:

Inductively coupled plasma mass spectrometry

iv:

Intravenous

MMP:

Matrix metalloproteinases

NSAID:

Non-steroidal anti-inflammatory drug

PBS:

Phosphate buffer solution pH 7.4

RCF:

Relative centrifugal force

tmax :

Time for maximum concentration

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Acknowledgments

This work was supported by the Danish Medicinal Research Council.

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Authors and Affiliations

  1. Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark

    Anna Buus Frost, Susan Weng Larsen, Jesper Østergaard, Stefan Stürup & Claus Larsen

  2. Clinical Pharmacology and Pharmacokinetics, H. Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark

    Frank Larsen

  3. Department of Large Animal Sciences, Faculty of Life Sciences, University of Copenhagen, Højbakkegård Allé 5, DK-2630, Taastrup, Denmark

    Maj Halling Thomsen & Pia Haubro Andersen

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  1. Anna Buus Frost
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  2. Frank Larsen
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  3. Susan Weng Larsen
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  8. Claus Larsen
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Correspondence to Claus Larsen.

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Frost, A.B., Larsen, F., Larsen, S.W. et al. The Pharmacokinetics of the Weakly Protein-Bound Anionic Compound Diatrizoate in Serum and Synovial Fluid of the Horse. Pharm Res 27, 143–150 (2010). https://doi.org/10.1007/s11095-009-9988-x

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  • DOI: https://doi.org/10.1007/s11095-009-9988-x

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