Bladder Tissue Pharmacokinetics of Intravesical Mitomycin C and Suramin in Dogs

Abstract

Abstract. Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy.

Potential of imaging analysis in establishing skin concentration-distance profiles for topically applied FITC-dextran 4 kDa

“…However, the drug concentration at each depth of the skin has been predicted using various mathematical equations [13][14][15][16][17][18]. We previously reported that the cutaneous disposition of topically applied drugs could be predicted using the difference method based on Fick's 2 nd law of diffusion, and also that the average drug concentration in the stratum corneum and viable epidermis/dermis could be determined separately [19][20][21][22].…”

Mitomycin C: New Strategies to Improve Efficacy of a Well-Known Therapy

“…Some previous in vitro investigations showed a duplication time of 56 ± 3 and 59 ± 2 hours for RT4 and RT112 experimental transitional tumor cell lines, respectively, far lower than the expected 7 days (10, 11).…”

Lyso-thermosensitive liposomal doxorubicin for treatment of bladder cancer

“…Penetration of intravesical drugs is characterised by a steep drop in concentration across the bladder wall due to limited tissue permeability that leads to low drug concentrations in deep tissue layers where high drug concentrations are needed to combat tumours with limited chemosensitivity [5,6,11,33]. Wientjes et al [6] reported an exponential decline in DOX concentration in the perfused tissues below the urothelium following intravesical administration of DOX in patients and a high degree of inter-patient variability.…”

“…High drug concentrations are needed at depth in the bladder wall to treat invasive tumours that reside there [9]. The urothelium, which lines the bladder lumen, acts as a transport barrier that restricts passage of molecules such as urea and ammonia from the urine (as well as intravesical drugs) into systemic circulation [10][11][12]. In addition, glycosaminoglycans comprising the mucin layer overlying the urothelium may further inhibit transport of intravesical substances.…”

“…In addition, glycosaminoglycans comprising the mucin layer overlying the urothelium may further inhibit transport of intravesical substances. Indeed, studies have shown that drugs such as mitomycin C and doxorubicin (DOX) penetrate poorly across the urothelium limiting dosing of tumours [5,6,9,11]. As such, methods to enhance the permeability of the bladder wall or alternative routes for drug delivery are necessary.…”