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.

The pharmacokinetics of para‐aminosalicylic acid and its relationship to efficacy and intolerance

“…Adams et al . found no relationship between plasma PAS, acetyl‐PAS or glycine‐PAS concentrations and gastrointestinal intolerance, irrespective of PASER administration as 4 g twice daily or 8 g once daily 74 …”

“…Therefore, PAS plasma concentrations probably play little role in gastrointestinal intolerance to PAS. Data from intravenous PAS administration show that if gastrointestinal tract is bypassed, intolerance to PAS is minimized; because gastrointestinal intolerance requires the presence of PAS in the gastrointestinal tract 74 …”

“…Adams et al found no relationship between plasma PAS, acetyl-PAS or glycine-PAS concentrations and gastrointestinal intolerance, irrespective of PASER administration as 4 g twice daily or 8 g once daily 74. In addition, Jones administered 4.8-5.0% solution of crystalline NaPAS (equivalent to 24-25 g NaPAS), intravenously to TB patients and found it well tolerated with only mild gastrointestinal symptoms seen in about 7.4% (2/27) of patients, despite very high plasma PAS concentrations 3.…”

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians

“…The PK of PAS varies with the formulation. PAS salts are readily absorbed when administered orally and achieve higher C max in plasma than with PAS acid or the widely available granular slow-release PAS formulation (PASER) [ 188 , 192 , 193 , 194 ]. Under the influence of N-acetyltransferase 1, PAS undergoes first-pass metabolism to acetyl-PAS in the gut and liver, which might explain acetyl-PAS appearance in blood earlier than PAS [ 181 , 195 ].…”

“…With improving intolerance in mind, PASER is enteric-coated and designed to slowly release PAS in the intestine rather than in the stomach [ 187 ]. Furthermore, the gastrointestinal intolerance is neither related to plasma concentrations nor to the conjugated metabolites [ 182 , 194 , 196 , 199 , 200 ].…”