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Metabolic Activation of Temozolomide Measured in Vivo Using Positron Emission Tomography¹

Cancer Research United Kingdom Positron Emission Tomography Oncology Group, Imperial College London [A. S., G. D. B., E. O. A., C. S. B., P. P.] and Imaging Research Solutions Ltd. [F. B., S. O., S. K. L., A. S. O. R.], Hammersmith Hospital, London W12 0NN, United Kingdom; Medical Research Council Cyclotron Unit, Imperial College London, Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom [T. J.]; Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom [M. F. G. S.]; and Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, United Kingdom [E. N.]

The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting.

[¹¹C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3–4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [¹¹C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that ¹¹C in the C-4 position of [4-¹¹C-carbonyl]temozolomide would be converted to [¹¹C]CO₂ if the postulated mechanism of metabolic conversion was true resulting in lower [¹¹C]temozolomide tumor exposure. Paired studies were performed with both forms of [¹¹C]temozolomide in 6 patients with gliomas. Another PET scan with ¹¹C-radiolabelled bicarbonate was performed and used to account for the metabolites of temozolomide using a data-led analytical approach. Plasma was analyzed for [¹¹C]temozolomide and [¹¹C]metabolites throughout the scan duration. Exhaled air was also sampled throughout the scan for [¹¹C]CO₂. The percentage ring opening of temozolomide over 90 min was also calculated to evaluate whether there was a differential in metabolic breakdown among plasma, normal tissue, and tumor.

There was rapid systemic clearance of both radiolabelled forms of [¹¹C]temozolomide over 90 min (0.2 liter/min/m²), with [¹¹C]CO₂ being the primary elimination product. Plasma [¹¹C]CO₂ was present in all of the studies with [4-¹¹C-carbonyl]temozolomide and in half the studies with [3-N-¹¹C-methyl]temozolomide. The mean contributions to total plasma activity by [¹¹C]CO₂ at 10 and 90 min were 12% and 28% with [4-¹¹C-carbonyl]temozolomide, and 1% and 4% with [3-N-¹¹C-methyl]temozolomide, respectively. There was a 5-fold increase in exhaled [¹¹C]CO₂ sampled with [4-¹¹C-carbonyl]temozolomide compared with [3-N-¹¹C-methyl]temozolomide (P < 0.05). A decrease in tissue exposure [area under the curve between 0 and 90 min (AUC_{0–90 min})] to [¹¹C]temozolomide was also observed with [4-¹¹C-carbonyl] temozolomide compared with [3-N-¹¹C-methyl]temozolomide. Of potential therapeutic advantage was the higher [¹¹C]radiotracer and [¹¹C]temozolomide exposure (AUC_{0–90 min}) in tumors compared with normal tissue. [¹¹C]temozolomide ring opening over 90 min was less in plasma (20.9%; P < 0.05) compared with tumor (26.8%), gray matter (29.7%), and white matter (30.1%), with no differences (P > 0.05) between tumor and normal tissues.

The significantly higher amounts of [¹¹C]CO₂ sampled in plasma and exhaled air, in addition to the lower normal tissue and tumor [¹¹C]temozolomide AUC_{0–90 min} observed with [4-¹¹C-carbonyl]temozolomide, confirmed the postulated mechanism of metabolic activation of temozolomide. A higher tumor [¹¹C]temozolomide AUC_{0–90 min} in tumors compared with normal tissue and the tissue-directed metabolic activation of temozolomide may confer potential therapeutic advantage in the activity of this agent. This is the first report of a clinical PET study used to quantify and confirm the in vivo mechanism of metabolic activation of a drug.

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