Imaging the Distribution of Carbon‐11 Labeled Rifampicin, Isoniazid and Pyrazinamide in Baboons using PET

Abstract

PET imaging studies of carbon‐11 labeled rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in baboons have been performed to provide more direct insight into pharmacokinetics and biodistribution of drugs for tuberculosis (TB) treatment and these baboon studies is a prelude to human imaging studies. These investigations would help us to determine better regime to treatment TB especially CNS TB because of its limited accessibility. It is also hypothesized that such high specific activity radiotracers may also useful for determining the location of bacterial population in vivo since these drug are expected to accumulated with in the bacteria. We find that all drugs cleared rapidly from lungs and injected [11C]RIF accumulates in gall bladder while injected [11C]INH and [11C]PZA accumulate in bladder. This is consistent with mechanism of excretion. We also find organ distributions of each drug are different from plasma PK, which is from several fold to hundreds fold. All of three injected drugs demonstrated higher concentration in lung than plasma over the study frame. Estimation based on the weight of baboon and normal dose and assumption of no metabolite suggested: concentration of RIF in lung is at least 5 times higher than MIC90, INH is more than 10 times higher than MIC90 and PZA is 1–3 times higher than MIC90 against MTB. The ability to enter the brain decreases in the order PZA > INH > RIF. Estimation of brain concentration based on same assumption as lung suggested that concentration of RIF is 3–4 times over MIC90 and INH is more than 10 times over MIC90, while PZA is quite close to MIC90 against MTB. These data have important implications for treatment of TB and CNS TB and set the scene for additional studies in humans.