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Continuous intravenous infusion of ATP in humans yields large expansions of erythrocyte ATP pools but extracellular ATP pools are elevated only at the start followed by rapid declines

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Abstract

The pharmacokinetics of adenosine 5′-triphosphate (ATP) was investigated in a clinical trial that included 15 patients with advanced malignancies (solid tumors). ATP was administered by continuous intravenous infusions of 8 h once weekly for 8 weeks. Three values of blood ATP levels were determined. These were total blood (erythrocyte) and blood plasma (extracellular) ATP pools along with the initial rate of release of ATP into the blood plasma. We found that values related to erythrocyte ATP pools showed great variability (diversity) among individuals (standard deviation of about 30–40 % of mean at baseline). It was discovered that erythrocyte baseline ATP pool sizes are unique to each individual and that they fall within a narrow range in each individual. At the end of an 8 h continuous intravenous infusion of ATP, intracellular erythrocyte ATP pools were increased in the range of 40–60 % and extracellular ATP declined from elevated levels achieved at the beginning and middle of the infusion, to baseline levels. The ability of erythrocytes to sequester exogenously administered ATP to this degree, after its initial conversion to adenosine in the blood plasma is unexpected, considering that some of the adenosine is likely to have been degraded by in vivo catabolic activities or taken up by organs. The data suggest that administration of ATP by short-term intravenous infusions, of up to 4 h, may be a favorable way for elevating extracellular ATP pools. A large fraction of the total exogenously administered ATP is sequestered into the intracellular compartments of the erythrocytes after an 8 h intravenous infusion. Erythrocytes loaded with ATP are known to release their ATP pools by the application of previously established agents or conditions applied locally or globally to circulating erythrocytes. Rapid degradation of intravenously administered ATP to adenosine and subsequent accumulation of ATP inside erythrocytes indicate the existence of very effective mechanisms for uptake of adenosine from blood plasma. These in vivo studies offer an understanding as to how both adenosine and ATP can act as purinergic transmission signals. ATP levels in blood are always accompanied by adenosine formed by catabolism of ATP. The continuous uptake of adenosine enables both to act in transmission of sometimes opposite functions.

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Acknowledgments

We thank Dr. Adaling Ogilvie for a critical review of the manuscript.

Conflict of interest

A clinical trial entitled “A Phase I Study of the Safety and Pharmacokinetics of Adenosine 5’-Triphosphate (ATP) When Administered by Intravenous Infusion on a Multiple Weekly Dose Schedule to Patients with Advanced Malignancies (Solid Tumors)” was funded by ATP Therapeutics LLC. E.R. and E.H.A. have financial interest in the development of purine-based drugs.

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Authors and Affiliations

  1. ATP Therapeutics, LLC, 37 Hay Road, Belmont, MA, 02478, USA

    Eliezer Rapaport

  2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

    Anna Salikhova

  3. Artesian Cancer Center, Claremore, OK, 74017, USA

    Edward H. Abraham

  4. Artesian Cancer Center, El-Dorado, AR, 71730, USA

    Edward H. Abraham

Authors
  1. Eliezer Rapaport
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  2. Anna Salikhova
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  3. Edward H. Abraham
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Correspondence to Eliezer Rapaport.

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Rapaport, E., Salikhova, A. & Abraham, E.H. Continuous intravenous infusion of ATP in humans yields large expansions of erythrocyte ATP pools but extracellular ATP pools are elevated only at the start followed by rapid declines. Purinergic Signalling 11, 251–262 (2015). https://doi.org/10.1007/s11302-015-9450-y

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  • DOI: https://doi.org/10.1007/s11302-015-9450-y

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