In vitro metabolism study of a new nitrosyl ruthenium complex [Ru(NH.NHq)(terpy)NO]3+ nitric oxide donor using rat microsomes.
A new nitrosyl ruthenium complex [Ru(NH.NHq)(terpy)NO](3+) nitric oxide donor was recently developed and due to its excellent vasodilator activity, it has been considered as a potential drug candidate. Drug metabolism is one of the main parameters that should be evaluated in the early drug development, so the biotransformation of this complex by rat hepatic microsomes was investigated. In order to perform the biotransformation study, a simple, sensitive and selective HPLC method was developed and carefully validated. The parameters evaluated in the validation procedure were: linearity, recovery, precision, accuracy, selectivity and stability. Except for the stability study, all the parameters evaluated presented values below the recommended by FDA guidelines. The stability study showed a time-dependent degradation profile. After method validation, the biotransformation study was accomplished and the kinetic parameters were determined. The biotransformation study obeyed the Michaelis-Menten kinetics. The V(max) and K(m) were, respectively, 0.1625+/-0.010 micromol/mg protein/min and 79.97+/-11.52 microM. These results indicate that the nitrosyl complex is metabolized by CYP450.
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. deoliveira@usp.br
Anderson Rodrigo Moraes
AR
de Oliveira
Patrícia
P
da Fonseca
Carlos
C
Curti
Roberto Santana
RS
da Silva
Pierina Sueli
PS
Bonato
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000378:metabolism*; D017711:Nonlinear Dynamics; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012428:Ruthenium / Q000737:chemistry / Q000378:metabolism*
C544426:(Ru(NH.NHq)(terpy)NO)3; D020030:Nitric Oxide Donors; D009942:Organometallic Compounds; D009249:NADP; D012428:Ruthenium