Pharmacokinetics and neutrophil toxicity of paclitaxel orally administered in mice with recombinant interleukin-2.
OBJECTIVE
Intrinsic P-glycoprotein (P-gp) expression in the gut limits paclitaxel uptake and, thus, its bioavailability when administered orally. Interleukin-2 has been reported to be a P-gp modulator in vitro and in vivo in mice. In the work described here, the effects of interleukin-2 pretreatment on pharmacokinetics and toxicity of paclitaxel orally administered were investigated.


METHODS
For the pharmacokinetic study, 96 mice were allocated to two groups receiving either 10 mg/kg of paclitaxel by the oral route alone or 16.5 microg of human recombinant interleukin-2 (rIL2) by the intraperitoneal route twice daily for 3 days and then paclitaxel. Pharmacokinetic profiles were analysed first by the Bailer method, and then using a compartmental approach. For the toxicity study, 90 Swiss mice were allocated to three groups receiving paclitaxel (10 mg/kg orally), rIL2 alone (16.5 microg i.p. twice daily for 3 days, control group), or both treatments. Haematological parameters were measured and the three groups were compared using the Bailer method. A Bonferroni correction was applied to the test.


RESULTS
A complex absorption of paclitaxel was revealed. The Bailer method showed that the mean area under the curve (AUC) values over 0-24 h were not significantly different in the two groups, despite a trend to reduced AUC in the pretreated group. The AUC over 0-0.5 h was significantly higher in the group pretreated with rIL2, but represented only a fraction of total exposure. These results were confirmed by the compartmental analysis. The elimination rate constant remained the same across both groups. rIL2 thus increased paclitaxel absorption for the 15 min following oral intake of the drug but did not enhance the overall exposure.


CONCLUSIONS
We found that a 3-day pretreatment with rIL2 had some in vivo inhibitory effects on P-gp activity for a short period after oral dosing of paclitaxel. Those results encourage further investigation of the effect of rIL2 on the overall exposure of paclitaxel. On the other hand, it seems that the joint administration of the two drugs did not increase the risk of myelosuppression, which might be worth knowing to treat advanced cancers.
Jamois
Candice
C
Laboratoire de Pharmacologie, Service Pharmacie, Assistance Publique des Hôpitaux de Paris-Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier, 94800, Villejuif, France.
Comets
Emmanuelle
E
Mentré
France
F
Marion
Sylvie
S
Farinotti
Robert
R
Bonhomme-Faivre
Laurence
L
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009504:Neutrophils; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007376:Interleukin-2; D017239:Paclitaxel