Imipramine: Clinical effects and pharmacokinetic variability

The role of S‐mephenytoin 4'‐hydroxylase in imipramine metabolism by human liver microsomes: a two‐enzyme kinetic analysis of N‐ demethylation and 2‐hydroxylation.

“…Imipramine has been used widely as an antidepressant plus desipramine [3,4], although some studies have not over the last 30 years [1]. It is exclusively metabolised confirmed this relationship with regard to imipramine in the liver, the major metabolic pathways including [5,6].…”

“…3 The respective mean (± s.d.) kinetic parameters for the N-demethylation and 2-hydroxylation of imipramine derived from a two-enzyme kinetic analysis were: Km1 = 1.1 ± 0.4 and 1.6± 0.6 FM, Vmaxl = 0.11 ±0.03 and 0.15 ±0.07 nmol mg-'min-', and Vmax1/Kml = 0.10 ± 0.02 and 0.09 ± 0.04 ml mg-1 min-'; Km2 = 214 ± 84 and 257 ± 148 FM, Vmax2 = 2.22 ± 0.69 and 0.53 ± 0.15 nmol mg-1 min-1, and Vmax2/ Km2 = 0.011 ± 0.001 and 0.003 ± 0.002 ml mg-' min-l. 4 With regard to imipramine N-demethylation and 2-hydroxylation at 2 FM (representing high-affinity reactions) and at 400 FLM (representing low-affinity reactions), only N-demethylation at 2 FM showed a close correlation with the 4'-hydroxylation of S-mephenytoin (r, = 0.952, P < 0.01; n = 10 livers).…”

“…3 The respective mean (± s.d.) kinetic parameters for the N-demethylation and 2-hydroxylation of imipramine derived from a two-enzyme kinetic analysis were: Km1 = 1.1 ± 0.4 and 1.6± 0.6 FM, Vmaxl = 0.11 ±0.03 and 0.15 ±0.07 nmol mg-'min-', and Vmax1/Kml = 0.10 ± 0.02 and 0.09 ± 0.04 ml mg-1 min-'; Km2 = 214 ± 84 and 257 ± 148 FM, Vmax2 = 2.22 ± 0.69 and 0.53 ± 0.15 nmol mg-1 min-1, and Vmax2/ Km2 = 0.011 ± 0.001 and 0.003 ± 0.002 ml mg-' min-l. 4 With regard to imipramine N-demethylation and 2-hydroxylation at 2 FM (representing high-affinity reactions) and at 400 FLM (representing low-affinity reactions), only N-demethylation at 2 FM showed a close correlation with the 4'-hydroxylation of S-mephenytoin (r, = 0.952, P < 0.01; n = 10 livers).5 Concentrations up to 250 FM S-mephenytoin inhibited the N-demethylation of imipramine (2 FLM), but no further inhibition was observed using concentrations from 250 to 750 FIM.6 Imipramine inhibited S-mephenytoin 4'-hydroxylation competitively with a Ki value of 12.5 FM. 7 The results suggest that the cytochrome P450 responsible for the 4'-hydroxylation of S-mephenytoin is partially involved in the metabolism of imipramine as one of the high-affinity components of its N-demethylation.…”

Effects of albumin and .ALPHA.1-acid glycoprotein on the transport of imipramine and desipramine through the blood-brain barrier in rats.

“…With regard to the reference compound, 14C-butanol, the maximal extraction (ER ,max) was reported to be 100%. 26,27) The relationship between ER.max and the extraction at 15 s ER(15S)is defined as28) (2) where kefflux is the efflux rate constant for 14 C-butanol (0.67 min -1).29) Substitution of the values for ER .max and with t = 10 s (the time between bolus entry into the brain and decapitation), into Eq. 2 gives ER(15s = 90% for…”

The Measurement of Plasma Tricyclics in a Saudi Population

“…It is these genetically determined pharmacokinetic characteristics and the physiochemical composition of the drug that produce the marked individual variations in steady-state plasma levels which are so typical of tricyclic drugs. 2 Studies by Glassman et al 3 and Reisby et al 4 show a linear or sigmoid relationship between blood level and clinical outcome. Imipramine and its demethylated metabolites were measured, and it was found that when the combined level of these two compounds exceeded 200 ng/mL of plasma, more patients responded favorably than at lower levels.…”