4.1.1. Humans

Fellstrom et al. (1987) measured pentosan polysulfate sodium in plasma and in urine by radioassay after intravenous and oral administration in a group of eight healthy volunteers. After intravenous administration of 40 mg of pentosan, plasma clearance was 49.9 ± 6.6 mL/minute, of which renal clearance constituted 4.2 ± 1.2 mL/minute. Only 8% of the intravenous dose was recovered in the urine, suggesting that there was extensive metabolism. After daily oral dosing with 400 mg of pentosan, steady-state trough plasma concentrations were low (20–50 ng/mL), and bioavailability was 0.5–1%.

The oral bioavailability of pentosan was investigated in 18 healthy young male volunteers who received pentosan as an intravenous dose of 50 mg, or an oral dose of 1500 mg, or a placebo (Faaij et al., 1999). Intravenously administered pentosan significantly increased activated partial thromboplastin time and the activity of anti-factor Xa, hepatic triglyceride lipase, and lipoprotein lipase compared with placebo in a magnitude comparable to other heparin-like compounds administered intravenously. Orally administered pentosan did not influence any of the parameters compared with placebo.

MacGregor et al. (1984) studied the catabolism of pentosan polysulfate sodium. Five healthy male volunteers were given [¹²⁵I]-labelled pentosan in conjunction with unlabelled pentosan at a dose of 0.1, 1, 7, or 50 mg intravenously. The half-lives for doses of 0.1–7 mg ranged from 13 to 18 minutes. At a dose of 50 mg, the half-life was 45 minutes. Tissue distribution studies showed that most of the radiolabelled material was localized in the liver and spleen. Pentosan was desulfated in the liver and spleen and depolymerized in the kidney, and it is likely that desulfation and depolymerization of pentosan is saturable.

Simon et al. (2005) studied two groups of eight healthy fasted female volunteers who sequentially received a single oral dose of 200 µCi of [³H]-labelled pentosan supplemented with 300 mg of unlabelled pentosan, or 300 µCi of [³H]-labelled pentosan supplemented with 450 mg of unlabelled pentosan. Most (84%) of the administered oral dose was excreted in the faeces as intact pentosan, and a smaller percentage (6%) was excreted in the urine as pentosan of low relative molecular mass and desulfated pentosan.

Excretion of pentosan was studied in 34 female patients with interstitial cystitis who were receiving long-term treatment with pentosan (Erickson et al., 2006). The median concentration of pentosan in the urine of these patients was 1.2 µg/mL (range, 0.5–27.7 µg/mL). All the pentosan recovered from the urine of these patients was of low relative molecular mass.

4.1.2. Experimental systems

In a pharmacokinetic study of pentosan in New Zealand rabbits, [¹²⁵I]-labelled pentosan as marker was injected simultaneously with increasing doses of unlabelled pentosan (Cadroy et al., 1987). The data indicated that prolongation of the half-life of pentosan with increasing doses resulted from progressive reduction in the clearance of the drug, with a constant volume of distribution.

Some studies of distribution were oriented towards the pharmacological application of pentosan in the treatment of interstitial cystitis. Kyker et al. (2005) used fluorescently labelled chondroitin sulfate to track the distribution of glycosaminoglycans administered intravesically to C57BL/6NHsd mouse bladder that had been damaged on the surface. Bladder damaged by trypsin or hydrochloric acid bound the labelled chondroitin sulfate extensively on the surface, with little penetration into the bladder muscle.

In rabbits given 1–1.2 mg of pentosan by intravenous administration, median recovery in the urine was 47.2% (range, 19.7–73.2%) for unfractionated pentosan, 74.6% (range, 31.4–96.3%) for pentosan of low relative molecular mass, and 3.3% (range, 2.5–5.0%) for pentosan of high relative molecular mass. In rabbits given 1.0–1.2 mg pentosan by oral administration, median recovery in the urine was 7.45% (range, 2.1–46.0%) for pentosan of low relative molecular mass, and 0.1% (range, 0.0–0.3%) for pentosan of high relative molecular mass (Erickson et al., 2006).

Sprague-Dawley rats were given [³H]-labelled pentosan orally or intravenously at a dose of 5 mg/kg bw, and killed 1 or 4 hours later, respectively. Autoradiography indicated extensive distribution of radiolabel in the whole animal after intravenous administration, with notable labelling of connective tissues, and low activity in bone and cartilage. There was a high concentration of radiolabel in the urine, and preferential localization of radiolabel to the lining of the urinary tract. After oral administration, the tissue distribution of radiolabel was similar, but activity was lower (Odlind et al., 1987).

4.2.1. Humans

No data were available to the Working Group.

4.2.2. Experimental systems

4.3.1. Effects on cellular physiology

Pentosan polysulfate sodium can antagonize the binding of fibroblast growth factor-2 (FGF-2) to its cell surface receptors, and has been shown to modulate the angiogenic activity of FGF-2 in tumours in humans and mice. Jerebtsova et al. (2007) studied the role of FGF-2 and pentosan in the pathogenesis of intestinal bleeding in mice. The results indicated that high steady-state levels of circulating FGF-2, plus anticoagulant activity, are needed to induce lethal intestinal bleeding in mice.

Treatment with pentosan prevents the progression of nephropathy in streptozotocin-induced diabetes in ageing C57B6 mice by decreasing albuminuria, renal macrophage infiltration, and expression of tumour necrosis factor-α (Wu et al., 2011).

Zugmaier et al. (1992) concluded that pentosan is an in-vitro inhibitor of a variety of heparin-binding growth factors released from tumour cells. Of seven tumour cell lines tested, six (breast cancer: MDA-MB-231, MDA-MB-435, MDA-MB-468; lung cancer: A-549; prostate cancer: DU-145; and epidermoid carcinoma: A-431) were resistant to pentosan in soft-agar cloning assays, and did not appear to depend on autocrine stimulation by the heparin-binding growth factors. In contrast to this resistance in vitro, subcutaneous growth of tumours from all cell lines in athymic nude mice was inhibited in a dose-dependent fashion by daily intraperitoneal injections of pentosan.

Pentosan inhibits virus adsorption to cells in vitro as demonstrated by monitoring the association of radiolabelled HIV-1 virions with MT-4 cells (Baba et al., 1988).

4.3.2. Effects on cell proliferation

Elliot et al. (2003) observed that pentosan has marked effects on the growth and extracellular matrix of smooth-muscle cells cultured from human prostate. Pentosan decreased cell proliferation and extracellular-matrix production. This suggested that the drug may have therapeutic potential in relation to benign prostatic hyperplasia.

The results of treatment of three prostate-cancer cell lines (LnCaP, PC3, and DU145) with pentosan have been reported (Zaslau et al., 2006). In LnCaP cells, there was a mean inhibition of growth of 12% ± 7% at 24 hours (P = 0.025), and 20% ± 15% at 72 hours (P < 0.001). Similar inhibition was observed in the other two cell lines.

Rha et al. (1997) reported that growth of gastric-cancer cell lines expressing midkine, a novel heparin-binding growth/differentiation factor, was inhibited by pentosan, which was described as a heparin-binding blocking agent.

Zaslau et al. (2004) reported that pentosan significantly inhibited the growth of ZR75-1 breast-cancer cells; however, a significant increase in cell proliferation (25% ± 2%; P < 0.001) was observed in estrogen-independent MCF-7 breast-cancer cells.

The effects of pentosan on tumour growth, hyperprolactinaemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats was described by Mucha et al. (2002). Long-term treatment with pentosan did not cause any changes in pituitary weight, serum prolactin concentration, or density of microvessels. However, there was an increase in the number of apoptotic bodies within the anterior pituitary.

The mechanism of cell motility inhibition by pentosan appears to be independent of cytoskeletal structural alterations, including changes in microfilament and microtubule networks (Pienta et al., 1992). In vitro, pentosan altered cellular contacts with the extravascular matrix and inhibited cell motility. In vivo, pentosan prolonged survival of male rats injected with highly metastatic cells.