CYP-dependent metabolism of antitumor pyrazolo[3,4-d]pyrimidine derivatives is characterized by an oxidative dechlorination reaction.
The aim of this study is to investigate the metabolic (cytochrome P450-dependent) behaviour of pyrazolo[3,4-d]pyrimidines 1-10 dual Abl/Src kinase inhibitors. All the compounds demonstrate good metabolic stability both in human liver (HLM) and in rat liver (RLM) microsomes. Moreover, all the tested molecules undergo the same metabolic CYP-dependent reactions, namely oxidative dechlorination and N-dealkylation. These metabolic pathways are fully characterized for compound 1. In HLM, the dehalogenated metabolite accounts for about 87% of the full 1 metabolism, while the N-dealkylated metabolite accounts for 12%. Inhibition studies performed using different CYP-inhibitors indicate that the 3A family is the isoenzyme family most involved in pyrazolo[3,4-d]pyrimidine metabolism. This observation is confirmed by studies performed by using CYP3A selective substrates. Furthermore kinetic analysis performed in RLM, HLM and cDNA CYP3A4 shows that the affinity of CYPs towards compound 1 is similar in all the tested preparations (Km = 32.7, 21.8, and 48.7 µM, respectively).
Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena.
Claudio
C
Zamperini
Elena
E
Dreassi
Giulia
G
Vignaroli
Marco
M
Radi
Stefania
S
Dragoni
Silvia
S
Schenone
Francesca
F
Musumeci
Massimo
M
Valoti
Riccarda
R
Antiochia
Maurizio
M
Botta
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D003640:Dealkylation; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human