Regional lymphatic drug exposure following intraperitoneal administration of 5-fluorouracil, carboplatin, and etoposide.
Intraperitoneal (i.p.) administration of chemoterapeutic agents results in greater total drug exposures in the peritoneal cavity than in plasma. A study on the drug exposure for i.p. lymphatics of pigs, receiving 5-fluorouracil (5-FU), etoposide (VP-16) and carboplatin (CBDCA) by the i.p. route was conducted. Drug concentrations in peritoneal fluid, plasma, and thoracic duct lymph were monitored over the ensuing 3 h. 5-FU appeared rapidly in thoracic duct, lymph and plasma. The lymph concentration declined after 20 min while the plasma concentration remained stable. CBDCA reached a stable concentration in lymph and plasma after 60 min. VP-16 peaked in the lymph after 20 min, whereas the plasma concentration continued to rise for 150 min; the peritoneal half-life for VP-16 was too long for clearance to be defined. Total drug exposure (AUC) was for 5-FU 5.7-fold greater for lymph than for plasma and for CBDCA equal in both compartments. VP-16 had a 2.1-fold higher AUC for lymph than for plasma. The results indicate that the i.p. route of administration results in a greater exposure of the lower thoracic duct lymph than the plasma to 5-FU, produces only a marginally increased exposure to VP-16, and results in no difference for CBDCA. The efficacy of 5-FU is a function of total drug exposure. The results reported provide a strong rationale for evaluating the adjuvant use of i.p. 5-FU in colorectal and gastric carcinoma.
Lindnér
P
P
Department of Surgery, Sahlgrenska Hospital, Göteborg, Sweden.
Heath
D D
DD
Shalinsky
D R
DR
Howell
S B
SB
Naredi
P
P
Hafström
L
L
D000818:Animals; D001202:Ascitic Fluid / Q000737:chemistry; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D007274:Injections, Intraperitoneal; D008196:Lymph / Q000737:chemistry*; D008198:Lymph Nodes / Q000737:chemistry; D010537:Peritoneum / Q000378:metabolism*; D010539:Permeability; D013552:Swine
D005047:Etoposide; D016190:Carboplatin; D005472:Fluorouracil