Vasopressin modulation of peritoneal, lymphatic, and plasma drug exposure following intraperitoneal administration.
i.p. administration of cytotoxic drugs for the treatment of regionally confined cancers results in a greater total drug exposure [area under the concentration x time curve (AUC)] for the peritoneal fluid and regional lymphatics than for plasma. We sought to augment the relative advantage of i.p. administration further through modulation of peritoneal clearance by reduction in splanchnic blood flow. Pigs were treated with 5-fluorouracil, etoposide (VP-16), and carboplatin (CBDCA) alone by the i.p. route or with the same drugs in combination with i.v. lypressin, a synthetic vasopressin analogue, which reduces splanchnic blood flow. Drug concentrations in peritoneal fluid, plasma, and thoracic duct lymph were monitored over the ensuing 6 h. The pharmacokinetics of 5-fluorouracil were not altered by vasopressin; however, vasopressin increased the peritoneal fluid:plasma AUC ratio for CBDCA from 30.6 +/- 5.6 to 70. 6 +/- 7.4 (P < 0.01) and increased the lymph:plasma AUC ratio from 1.1 +/- 0.4 to 2.6 +/- 0.22 (P < 0.05). In the case of VP-16, vasopressin increased the peritoneal fluid:plasma AUC ratio from 129 +/- 35 to 350 +/- 76 (P < 0.05) and the lymph:plasma AUC ratio from 2.1 +/- 0.6 to 10.6 +/- 3.5 (P < 0.05). Concurrent i.v. administration of vasopressin can increase the pharmacokinetic advantage of the i.p. route of administration of CBDCA and VP-16 markedly in the pig model. These data suggest that the strategy of concurrent i.p. administration of CBDCA or VP-16 plus an agent that reduces splanchnic blood flow may increase the dose intensity in the abdominal cavity and intraabdominal lymphatic tissue substantially without increasing systemic toxicity.
Lindnér
P
P
Department of Surgery, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.
Heath
D
D
Howell
S
S
Naredi
P
P
Hafström
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D008196:Lymph / Q000378:metabolism*; D010537:Peritoneum / Q000378:metabolism*; D013552:Swine; D014667:Vasopressins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014667:Vasopressins; D005047:Etoposide; D016190:Carboplatin; D005472:Fluorouracil