Measurement of nitrobenzylthioinosine in plasma and erythrocytes: a pharmacokinetic study in mice |
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Authors: | Wendy P Gati Alan R P Paterson |
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Institution: | (1) Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 Tel. (403) 492-3609; Fax (403) 492-4325, CA |
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Abstract: | Purpose: Nitrobenzylthioinosine (NBMPR), a potent inhibitor of nucleoside transport in many cell types, modulates the in vivo disposition
of several cytotoxic nucleoside analogs. In this study, a radioligand binding assay was developed for measurement of the NBMPR
content of plasma and erythrocytes. Methods: The assay was based on the competition between NBMPR and 3H]NBMPR for high-affinity sites on human erythrocyte membranes. With this assay, we followed in mice changes in the NBMPR
content of blood plasma and erythrocytes, following the intraperitoneal injection of the disodium salt of NBMPR 5′-monophosphate
(NBMPR-P), a prodrug form of NBMPR. Results: The radioligand binding assay was able to measure precisely as little as 2.5 pmol of NBMPR, allowing the direct determination
of NBMPR concentrations in plasma as low as 16 nM. As few as 8 × 103 molecules of NBMPR per cell could be determined in erythrocytes. The NBMPR content of plasma from mice injected with NBMPR-P
was maximal at about 20 min after injection and declined to <0.2% of the peak value by 10 h. Erythrocyte-associated NBMPR
was also maximal at 20 min, and declined to 11% of the peak value by 10 h after injection. Time courses for the disappearance
of NBMPR from plasma and erythrocytes were monoexponential and yielded half-life values of 0.39 h and 0.68 h, respectively,
an apparent volume of distribution of 0.61 l/kg, and a clearance of 1.1 l/h per kg. Conclusions: The radioligand binding assay is a sensitive and facile method for monitoring NBMPR concentrations in mammalian plasma and
tissue extracts.
Received: 20 August 1995 / Accepted: 17 December 1996 |
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Keywords: | Nitrobenzylthioinosine (NBMPR) Nucleoside transport Radioligand binding assay Pharmacokinetics of NBMPR |
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