Effect of Urine pH on the Stability of Doxorubicin and its Recovery from Bladder Instillations

Abstract

Doxorubicin (1 mg/ml) was shown to be stable when added to urine samples with a mean natural pH of 5.4 and in urine buffered to a mean pH of 4.6. However, at alkaline pH (mean = 8.1) there was a biphasic degradation of doxorubicin (mean t1/2 = 3.24 and 89 h respectively). The data indicate that buffering intravesical doxorubicin to pH 4.6 (acetate buffer) or pre-dosing of patients with ammonium chloride may minimise loss of active drug during the time for which the drug is retained in the bladder. Recovery of doxorubicin following 1 hour's retention in the bladder was similar (77%) for doses of 38/48 or 78 mg. It is suggested that a dose of 50 mg (1 mg/ml) is sufficient to ensure an adequate delivery of active drug to the bladder wall.

Polyacrylic Acid Functionalized Nanographene as a Nanocarrier for Loading and Controlled Release of Doxorubicin Hydrochloride

“…In addition, the DOX molecule has an -NH 2 group, so its hydrophilicity becomes higher under acidic conditions, which explains why the release ratio of DOX in pH 2 was about twice that of in pH 7. However, DOX would become extremely volatile and decompose easily under alkaline conditions when meeting the light [44,45], which may be the reason why the release ratio of DOX in pH 2 is about seven times of in pH 10. The pH-dependent drug release from PAA-GNS could be exploited for drug delivery applications since the micro-environments in the extracellular tissues of tumors and intracellular lysosomes and endosomes are acidic, which will afford active drug release from PAA-GNS delivery vehicles.…”

Intravesical Treatments of Bladder Cancer: Review

“…The urine pharmacokinetic model provides the tool to depict changes in urine drug concentrations due to changes in physiological parameters that can vary from patient to patient (e.g., residual urine volume, urine pH, urine production rate) and changes in drug-related parameters (e.g., dose, dosing volume, degradation in acidic or basic environment). It is noted that most of the small molecule drugs used in intravesical chemotherapy have pH-dependent stability, e.g., MMC is unstable in pH < 5 or pH > 8 ( 64 , 65 ), thiotepa and its active metabolite are unstable in acidic pH (<5) and stable at alkaline pH (8.4) ( 66 , 67 ), whereas doxorubicin is more stable in acidic pH (5.4) than in alkaline pH (8.1) ( 68 ). pH also affects the antitumor activity, e.g., MMC is more active at acidic pH in monolayer cultures (but no pH dependent-effect in 3-dimensional cultures) ( 69 ), epirubicin is more active at alkaline pH (8.0) than at lower pH (6.0) ( 70 ).…”

Intravesical Chemotherapy and Chemohyperthermia in Non-Muscle-Invasive Bladder Cancer; An Overview on Drug Administration Technologies and Pharmacokinetics

“…MMC is stable at pH 6 [21,22], Thiotepa and its active metabolite at alkaline pH (8.4) [23,24], whereas Doxorubicin is more stable in acidic pH [25]. The antitumor activity is also affected by pH.…”