European Urology European Urology 44 (2003) 615–619 PharmacokineticsofIntravesicalGemcitabine: APreclinicalStudyinPigs J.A. Witjes * , J.L.J. Vriesema, A.G. van der Heijden, G.J. Peters, J.A. Schalken Department of Urology, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands First published online 29 July 2003 Abstract Introduction: Gemcitabine is a deoxycytidine analogue, used intravenously in the treatment of several tumours, including transitional cell carcinoma of the bladder. It has been shown to be effective and well tolerated when given systemically. We investigated the use of this agent administered intravesically in pigs for histological studies of the bladder and pharmacokinetic research. Material and Methods: Two groups of 5 female pigs each received once 175 mg and 350 mg gemcitabine intravesically for 2 hours. A third group of 5 pigs received 350 mg gemcitabine weekly for 6 weeks. Animals were observed for clinical signs of toxicity. Blood was withdrawn for gemcitabine pharmacokinetics and in group 3 also for peripheral blood counts. The animals were euthanized 24 hours after (the last) instillation. Histological examination of the bladder wall was performed. Results: Doses of 175 and 350 mg gemcitabine were well tolerated. The animals showed no signs of deterioration of their well-being. Peripheral blood counts showed no signs of immunosuppression in the third group. In none of the pigs systemic absorption was seen, up to 4 hours after the beginning of instillation. Histology showed in all cases normal bladder wall histology, except for some cases with mild signs of infection (mainly group 3). Conclusion: The use of gemcitabine as an intravesical agent in pigs is well tolerated, has no bladder toxicity and is not absorbed systemically. # 2003 Elsevier B.V. All rights reserved. Keywords: Intravesical chemotherapy; Gemcitabine; Animal; Pharmacokinetics 1. Introduction Superficial transitional cell carcinoma (TCC) of the bladder has a high and rising incidence, and an even higher prevalence because of its high recurrence rate after primary transurethral resection (TUR). Intravesi- cal instillations are used to lower the recurrence rate and the chance of progression to muscle invasive disease. For intravesical instillations the choice is in principal twofold: intravesical chemotherapy or intra- vesical immunotherapy. Intravesical chemotherapy reduces the risk of recurrence in the first years after therapy, but this effect becomes smaller after a longer period of follow up. In a large meta-analysis Pawinski et al. showed that after 5 years of follow up the treated group only had a 6% lower recurrence rate as compared to the none treated group [1]. Moreover, it has been shown repeatedly that intravesical chemotherapy has no influence on progression. Intravesical immunother- apy is practically synonymous for intravesical BCG. Of intravesical BCG it is clear that the reduction of the recurrence rate after TUR is significantly higher as compared to intravesical chemotherapy, although at the cost of more and more severe side effects [2]. Addi- tionally, recent data have shown that BCG can even delay tumour progression [3]. In all, there seems to be a need for new drugs in the treatment of patients with superficial bladder cancer, with higher efficacy and/or less toxicity. On of these newer drug is gemcitabine, a novel deoxycytidine analogue. Gemcitabine has been used in several tumours, and it has been shown to be effective and well tolerated when given systemically. * Corresponding author. E-mail address: f.witjes@uro.umcn.nl (J.A. Witjes). 0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0302-2838(03)00372-5