November 19, 2002
This study generated much interest during the pharmacology session. The authors have developed a test to measure intracellular levels of phosphorylated nucleoside analogue reverse transcriptase inhibitors (NRTIs). While using this test to measure various NRTIs, they seemed to stumble upon an intriguing discovery that they further investigated.
Monitoring of NRTI plasma levels has largely been considered ineffective since it is the phosphorylated intracellular form that is active and has been much harder to measure. To meet this challenge, the authors developed such an assay and tested it with various drugs of the NRTI class including AZT (ZDV, zidovudine, Retrovir) and d4T (stavudine, Zerit). In other abstracts presented at the conference, the assay is described in detail (abstracts P171, P172). Briefly, it is a direct liquid chromatography coupled with tandem mass spectrometry (hence, abbreviated to LC/MS/MS) assay that requires a relatively large 8 mL blood draw. Multiple NRTI can be measured.
When testing patients receiving AZT, the authors found that not only was AZT-TP found in the cells, but smaller quantities of d4T-TP as well. The experiments were repeated and the authors attempted to rule out any confounding factors that might cause a spurious result. After numerous samples were assayed, the authors concluded that when AZT is administered, both AZT-TP and d4T-TP are produced in the cell with the concentration of d4T-TP ranging from 3-37 percent of the AZT-TP. It was consistently far less than the amount of AZT-TP. When d4T was given, AZT-TP was not produced.
It is important to note that this has not been described by other techniques or by other researchers using this new assay. We need to keep in mind that there is currently no form of conformation for these findings. If indeed this observation is true, what clinical relevance does it have? In discussions with colleagues many considerations were raised. Are these levels of d4T responsible for most/part of the effect/toxicity of AZT? Is the greater efficacy/toxicity seen in some patients receiving AZT actually a result of the relatively higher levels of d4T-TP produced? Can we consider a patient who received AZT to really having been exposed to d4T as well? Does this provide some insight into AZT/d4T cross-resistance?
We probably need to wait to get more conformation of these findings and I am not sure this really has any immediate bearing on our routine patient management. What should not be overlooked due to these intriguing results is the original objective of the authors -- a new assay to measure intracellular phosphorylated NRTI levels. If indeed this assay is reliable and not expensive, it could open the door to therapeutic drug monitoring for NRTIs.
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