Pharmacokinetics of Para‐Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance

Abstract

Para‐aminosalicylic acid (PAS), often the last drug remaining for treatment of drug‐resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow‐release enteric coated formulation, and its metabolites acetyl‐PAS and glycine‐PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug‐resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow‐release enteric‐coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman s correlation test assessed the relationship between maximum plasma concentrations (Cmax) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42‐68.55 mg/L) following 4 g twice daily; (62.69‐102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl‐PAS and glycine‐PAS. Twenty‐six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl‐PAS Cmax and bloating (rho = –0.448; P = .025) and diarrhea (rho = –0.407; P = .044) for the twice‐daily regimen and a similar inverse association found for glycine‐PAS and diarrhea (rho = –0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.