Abstract
The purpose of this in vitro study was to compare the degradation of gemcitabine (2’, 2’-difluorodeoxycytidine, dFdC), in Fresh Whole Blood (FWB) from humans, dogs, cats, and horses. A better understanding of the comparative degradation of gemcitabine may aid in the optimal design of therapeutic regimens in veterinary species. Fresh whole blood from humans, dogs, cats, and horses was spiked with dFdC and plasma was analyzed for dFdC and 2’, 2’-difluorodeoxyuridine (dFdU) by high performance liquid chromatography. In these species, there was an initial rapid degradation of dFdC with a concomitant proportional increase in dFdU. Degradation of gemcitabine appeared similar in humans, dogs, and horses (p>0.05) whereas metabolism was slower in the cat than human (p=0.014), dog (p=0.010), or horse (p=0.0015). Based on these in vitro findings, dosing schemes for humans, dogs, and horses may be similar. In contrast, gemcitabine degradation occurred more slowly in the cat; this difference may dictate a different dosing scheme for optimal response in this species.
Highlights
Gemcitabine (2’, 2’-difluorodeoxycytidine, dFdC) is a synthetic deoxycytidine nucleoside analog of the pyrimidine antimetabolite cytosine arabinoside. [1] It structurally differs from deoxycytidine due to the geminal fluorine molecules on the 2’ position of the furanose ring.[2]
[7] Catabolism of gemcitabine occurs through deamination by cytidine deaminase (CDA) to difluorodeoxyuridine, which is excreted in the urine [5,7,8,9]
Gemcitabine enters the cell by nucleoside transporters and is rapidly phosphorylated to its cytotoxic metabolite, Gemcitabine triphosphate (dFdCTP), in three sequential steps by deoxycytidine kinase and two nucleoside kinases [1,4,29]
Summary
Gemcitabine (2’, 2’-difluorodeoxycytidine, dFdC) is a synthetic deoxycytidine nucleoside analog of the pyrimidine antimetabolite cytosine arabinoside. [1] It structurally differs from deoxycytidine due to the geminal fluorine molecules on the 2’ position of the furanose ring.[2]. [1] It structurally differs from deoxycytidine due to the geminal fluorine molecules on the 2’ position of the furanose ring.[2] The main mechanism of action of gemcitabine is inhibition of DNA synthesis, which blocks the progression of cells through the G1-S phase of the cell cycle.[1,3] There is influx of gemcitabine through the cell membrane by active nucleoside transporters and metabolism of gemcitabine occurs intracellularly with rapid conversion to the active metabolite gemcitabine triphosphate (dFdCTP) [1,3,4]. [7] Catabolism of gemcitabine occurs through deamination by cytidine deaminase (CDA) to difluorodeoxyuridine (dFdU), which is excreted in the urine [5,7,8,9]. Cytidine deaminase is responsible for the rapid metabolic clearance of gemcitabine during clinical use [3] and CDA is known to be found in visceral organs and whole blood [5,10,11]. While gemcitabine has demonstrated efficacy in human cancers including non-small cell lung cancer [12] pancreatic cancer [13], breast cancer [14], and bladder cancer, [15] reports of the use of gemcitabine in veterinary oncology have been limited and veterinary species have not enjoyed the same efficacy that has been demonstrated in humans. [16,17,18,19,20,21,22]
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