To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS Six arms of three patients each with a non-muscle-invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5-3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High-pressure liquid chromatography/high-resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5-3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2-h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical trials.

Pharmacokinetic study to optimize the intravesical administration of gemcitabine

GONTERO, Paolo;CATTEL, Luigi;PAONE, tonia celeste;MILLA, Paola;BERTA, GIOVANNA;FIORITO, CHIARA;CARBONE, Francesco;MEDANA, Claudio;TIZZANI, Alessandro
2010-01-01

Abstract

To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS Six arms of three patients each with a non-muscle-invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5-3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High-pressure liquid chromatography/high-resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5-3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2-h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical trials.
2010
106
11
1652
1656
Bladder cancer; gemcitabine; non-muscle invasive; pharmacokinetics.
Gontero, Paolo; Cattel, Luigi; Paone, Tonia C.; Milla, Paola; Berta, Giovanna; Fiorito, Chiara; Carbone, Francesco; Medana, Claudio; Tizzani, Alessandro
File in questo prodotto:
File Dimensione Formato  
pre-print BJU int 2010.pdf

Accesso aperto

Descrizione: pre-print
Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 222.4 kB
Formato Adobe PDF
222.4 kB Adobe PDF Visualizza/Apri
BJU Int 2010.pdf

Accesso riservato

Descrizione: PDF editoriale
Tipo di file: PDF EDITORIALE
Dimensione 277.11 kB
Formato Adobe PDF
277.11 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/132910
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 14
social impact