Metabolism of [³H]pentosan polysulfate sodium (PPS) in healthy human volunteers

Abstract

Pentosan polysulfate sodium (PPS) is the active ingredient in ELMIRON, a drug approved for the relief of bladder pain associated with interstitial cystitis. The study objective was to characterize the pharmacokinetic and metabolic profiles of PPS following oral dosing of [3H]PPS. As specific assays for PPS do not exist, metabolic profiling was accomplished through multiple fraction collections and radiochromatographic techniques. Two groups of eight healthy female subjects sequentially received a single oral dose of 200 microCi [3H]PPS supplemented with 300 mg unlabelled PPS or 300 microCi [3H]PPS supplemented with 450 mg unlabelled PPS. Most of the administered dose (84%) was excreted in faeces as intact PPS, and a smaller percentage (6%) was excreted in urine. In summary, orally administered PPS was very poorly absorbed, with the majority of the drug being excreted in faeces as intact PPS and in urine as low molecular weight and desulfated PPS.

A potent oral P‐selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease

“…PPS is an orally absorbable semisynthetic sulfated polysaccharide that has structural and functional similarities to but considerably less anticoagulant activity than heparin, as well as potent blocking activity against cell adhesion to Pselectin [27][28][29]. PPS is approved as an oral agent in the US as Elmiron 1 (Ortho-McNeil, Raritan, NJ) for the treatment of interstitial cystitis and in Europe as SP54 1 (bene-Arzneimittel GmbH, Munich, Germany) for treatment of thrombotic and atherosclerotic disorders.…”

“…The short, 2-hr T max of PPS administered orally [27] allows for substantial short-term variation in its pharmacodynamic effects. This suggests that long-term prophylactic therapy with PPS might require divided doses or a single daily dose of a preparation that provides more prolonged exposure of the endothelium to the active pharmaceutical ingredient.…”

Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

“…The more significant improvements in microvascular blood flow from a single dose of PPS in the Phase I trial compared to the less significant changes from daily doses of PPS in the Phase II study might relate to the Phase II trial design in which each patient was to take study drug in the morning and report for LDV measurements at an unspecified time later in the day. The short, 2-hr T max of PPS administered orally [27] allows for substantial short-term variation in its pharmacodynamic effects. This suggests that long-term prophylactic therapy with PPS might require divided doses or a single daily dose of a preparation that provides more prolonged exposure of the endothelium to the active pharmaceutical ingredient.…”

Interstitial Cystitis

“…PPS has also been used intravesically based on the hypothesis that it replenishes the protective bladder lining composed primarily by glycosaminoglycans layer; additionally, only 6% of PPS is excreted in urine when given orally (61). A recent RCT showed that combined therapy of intravesical and oral PPS led to two-fold reduction in the severity of PBS/IC symptoms compared with oral therapy alone (87).…”

“…PPS treatment within 6 mo after PBS/IC diagnosis is associated with greater efficacy in comparison with late treatment (60). However, administration for a prolonged period may be required before clinical response is noted, since oral treatment leads to low concentration in the bladder; it has been shown that only 6% of PPS is excreted in urine (61). The most commonly reported side effects include nausea, diarrhea, headache, and alopecia (62).…”