Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding.
Intraperitoneal (i.p.) chemotherapy is a promising therapeutic method to improve the effectiveness of cisplatin in patients with ovarian cancer and peritoneum involvement. Intraperitoneal treatment can be intraoperatively performed just after a complete surgical resection of peritoneal tumor nodules. However, little is known regarding the pharmacokinetics of platinum during intraoperative i.p. chemotherapy (IIC). Serum and i.p. measurements of total and ultrafilterable platinum were performed to determined pharmacokinetic parameters in 11 consecutive patients who received a 2-h IIC with 50 mg/m cisplatin. Protein concentrations were determined in serum and peritoneal liquid at the same times. The cisplatin concentration required to kill OVCAR-3 human ovarian cancer cells and evaluation of cisplatin binding to proteins were determined in vitro. Platinum i.p. concentration decreased rapidly and quickly came under the cytotoxicity threshold (10 mg for 2 h). About 85% of i.p. and serum cisplatin was ultrafilterable during IIC. Platinum concentrations were closely related to protein concentrations. Due to the very low level of serum protein (almost 25 g/l), serum cisplatin binding during chemotherapy was very low (almost 25%), but increased with protein concentration recovery. These pharmacokinetic data show that a sufficient concentration to kill human ovarian cancer is not reached with a single i.p. bath containing 50 mg/m cisplatin for 2 h. A new protocol with a renewed bath and a higher cisplatin concentration is under investigation.
Royer
Bernard
B
Laboratoire de Pharmacologie Clinique, CHU Jean Minjoz, Besançon, France. bernard.royer@ufc-chu.univ-fcomte.fr
Guardiola
Emmanuel
E
Polycarpe
Emmanuel
E
Hoizey
Guillaume
G
Delroeux
Delphine
D
Combe
Marielle
M
Chaigneau
Loïc
L
Samain
Emmanuel
E
Chauffert
Bruno
B
Heyd
Bruno
B
Kantelip
Jean-Pierre
JP
Pivot
Xavier
X
D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001202:Ascitic Fluid / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007432:Intraoperative Period; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D011485:Protein Binding / Q000187:drug effects
D000970:Antineoplastic Agents; D001798:Blood Proteins; D002945:Cisplatin