Effects of rifampicin on porphyrin metabolism in healthy volunteers

Abstract

Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo‐controlled trial with 600‐mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14. Rifampicin increased urine pentaporphyrin concentration 3.7‐fold (mean 1.80 ± 0.6 vs. 6.73 ± 4.4 nmol/L, p = 0.003) in comparison with placebo. Urine coproporphyrin I increased 23% (p = 0.036). Faecal protoporphyrin IX decreased (mean 31.6 ± 23.5 vs. 19.2 ± 27.8 nmol/g, p = 0.023). The number of blood erythrocytes was slightly elevated, and plasma bilirubin, catabolic metabolite of haem, was decreased. In conclusion, rifampicin dosing elevated the excretion of certain urinary porphyrin metabolites and decreased faecal protoporphyrin IX excretion. As urine pentaporphyrin and coproporphyrin I are not precursors in haem biosynthesis, increased excretion may serve as a hepatoprotective shunt when haem synthesis or porphyrin levels are increased.

Various effects of repeated rifampin dosing on coproporphyrin levels in humans

“…2 Besides its impact on drug metabolizing enzymes and transporters, early findings by McColl et al 30 showed significantly higher urinary levels of markers for heme biosynthesis after long-term treatment with RIF. Moreover, Tolonen et al 10 reported an effect of multiple doses of RIF on the urinary and fecal porphyrin elimination, but no higher porphyrin levels were observed in plasma. The latter group performed their analysis 1 day after the last RIF administration, suggesting no direct inhibitory effect on OATP1B1.…”

“…8 In the same preclinical model, no influence on CP levels was observed in the period after a long-term treatment with RIF. 9 In humans, Tolonen et al 10 reported increased urinary CPI levels after 7-day RIF treatment. Unfortunately, their study was not designed to determine the corresponding blood CPI levels.…”

“…In humans, Tolonen et al 10 reported increased urinary CPI levels after 7‐day RIF treatment. Unfortunately, their study was not designed to determine the corresponding blood CPI levels.…”