Effect of several compounds on biliary excretion of paclitaxel and its metabolites in guinea-pigs.
The objective of this study was to evaluate the in vivo metabolic profile of paclitaxel and to examine the effect of potential co-administered drugs on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. We first investigated in vitro paclitaxel metabolism using liver microsomes obtained from various species to identify the most suitable animal model with a similar metabolism to humans. Then, in vivo paclitaxel metabolism was investigated in male guinea-pigs. The levels of paclitaxel and its metabolites were measured by high-performance liquid chromatography in bile samples from guinea-pigs after paclitaxel i.v. injection (6 mg/kg). We further evaluated the effects of various drugs (quercetin, ketoconazole, dexamethasone, cotrimoxazole) on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. This work demonstrated significant in vitro interspecies differences in paclitaxel metabolism. Our findings showed both in vitro and in vivo similarities between human and guinea-pig biotransformation of paclitaxel. 6alpha-Hydroxypaclitaxel, the main human metabolite of paclitaxel, was found in guinea-pig bile. After paclitaxel combination with ketoconazole or quercetin in guinea-pigs, the cumulative biliary excretion of paclitaxel and its metabolites up to 6 h was significantly decreased by 62 and 76%, respectively. The co-administration of cotrimoxazole or pretreatment with dexamethasone did not alter significantly cumulative biliary excretion. The guinea-pig is a suitable model to study metabolism and biliary excretion of paclitaxel, and to investigate in vivo drug interactions.
Bun
Sok-Siya
SS
Laboratory of Pharmacokinetics and Toxicokinetics, Faculty of Pharmacy, Marseille, France. siya.bun@pharmacie.univ-mrs.fr
Giacometti
Sarah
S
Fanciullino
Raphaëlle
R
Ciccolini
Joseph
J
Bun
Hot
H
Aubert
Claude
C
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D000975:Antioxidants / Q000494:pharmacology; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D005938:Glucocorticoids / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011794:Quercetin / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology
D000890:Anti-Infective Agents; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D005938:Glucocorticoids; D003907:Dexamethasone; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D011794:Quercetin; D017239:Paclitaxel; D007654:Ketoconazole