Protein Binding of First-Line Antituberculous Drugs [PublishAheadOfPrint]

Introduction: The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB). Its efficacy could be further improved by determining the free drug concentrations in plasma, knowing that only the unbound drug can freely penetrate to the tissues.

Methods: Using an ultrafiltration technique, we determined the protein binding (PB) extent and variability of the first-line anti-TB drugs when given simultaneously to TB patients, representing a real-life case scenario. We used clinical samples routinely received by our laboratory. Plasma proteins were also measured. A protein-free medium was used to determine the nonspecific binding.

Results: Plasma samples from 22 patients were included, of which plasma proteins were measured in 18 patients. The median PB was determined for rifampin (88%, range 72 – 91), isoniazid (14%, range 0 – 34), pyrazinamide (1%, range 0 – 7), and ethambutol (12%, range 4 – 24). Plasma proteins were not found to be significant predictors for the PB of first-line anti-TB drugs. Rifampin PB was positively correlated with its plasma concentration (p-value= 0.0051). Conversely, isoniazid PB was negatively correlated with its plasma concentration (p-value= 0.0417). Age was found to have a significant effect on isoniazid PB (p-value= 0.0376). No correlations were observed in pyrazinamide or ethambutol.

Conclusion: We have determined variable PB of rifampin, isoniazid, pyrazinamide, and ethambutol in patient plasma samples, with median values of 88, 14, 1, and 12%, respectively. In this small study, PB of rifampin and isoniazid are dependent on their plasma concentrations.

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