Intratumoural administration of cisplatin in slow-release devices: II. Pharmacokinetics and intratumoural distribution.
The pharmacokinetics of cisplatin in mice with s.c. RIF 1 tumours was studied after intratumoural (i.t.) administration of drug in solution and in different slow-release devices. The data were compared with those obtained after i.p. administration of cisplatin. The slow-release devices under test were manufactured from either starch (ST) or polymeric hydrogels with different water uptakes (named T1, T2 and T3). In vitro release from these devices was approximately 100% in 2 h for starch rods, 100% in 24 h for T3 hydrogels, 45% in 4 days for T2 hydrogels and less than 10% in 4 days for T1 hydrogels. In vivo release rates agreed well with the in vitro data for T1 and T2 rods and were slightly slower in vivo for the T3 rods. The ST rods released the drug 6 times slower in vivo than in vitro. Plasma concentrations after i.t. administration were lower than those measured after i.p. administration. Systemic exposure to both total and free platinum was reduced to 70% for i.t. as compared with i.p. administration. Tumour concentrations were 4 times higher after i.t. than after i.p. administration. Tumour and peak plasma levels of platinum increased with increasing release rates. With the faster-releasing formulations (ST and T3), tumour platinum concentrations were 100 times higher than after i.p. administration. With the slower releasing formulations (T1 and T2), total tumour platinum concentrations were 2 and 9 times higher, respectively, than after i.t. administration of cisplatin in solution. Platinum distribution within the tumour was homogeneous after i.p. administration. After i.t. administration of cisplatin in solution, platinum concentrations in the centre of the tumour were approximately 4 times higher than in peripheral tumour tissue. Implantation of cisplatin in T2 and T3 hydrogel rods resulted in large concentrations of platinum in the centre of the tumour (the site of implant), which decreased steeply towards the tumour periphery. In summary, i.t. administration of cisplatin solution produced better results than did systemic (i.p.) administration in terms of tumour versus plasma drug-concentration ratios. Administration of drug in slow-release rods proved even more advantageous, although this was offset by inhomogeneous drug distributions within the tumour.
Deurloo
M J
MJ
Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
Kop
W
W
van Tellingen
O
O
Bartelink
H
H
Begg
A C
AC
D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004343:Drug Implants; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D010984:Platinum / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D012878:Skin Neoplasms / Q000378:metabolism*; D013997:Time Factors
D003692:Delayed-Action Preparations; D004343:Drug Implants; D010984:Platinum; D002945:Cisplatin