title: In vitro and in vivo clinical pharmacology of dimethyl benzoylphenylurea, a novel oral tubulin-interactive agent.
abstract: Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented <2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-1000, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Smith
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Gurulingappa
authors.initials: G
authors.lastname: Hallur
authors.forename: Saeed
authors.initials: S
authors.lastname: Khan
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008782:Methylurea Compounds / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D019438:Ritonavir / Q000494:pharmacology; D013379:Substrate Specificity; D014404:Tubulin / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D009363:Neoplasm Proteins; D014404:Tubulin; C496369:dimethyl benzoylphenyl urea; D003577:Cytochrome P-450 Enzyme System; D019438:Ritonavir