The analysis and disposition of imipramine and its active metabolites in man

Abstract

Single oral and intramuscular (i.m.) doses of imipramine (IMI) were administered to four normal males. Serum and urine concentrations of IMI, desipramine (DMI) and their unconjugated 2-hydroxy metabolites were measured by high-pressure liquid chromatography (HPLC). Urinary conjugated 2-hydroxy metabolites were also measured after enzyme hydrolysis. Computer analysis of serum concentration and urinary excretion rate data allowed confirmation of drug and metabolite kinetics, and calculation of pharmacokinetic parameters. The rapid appearance of the metabolites in serum indicates that sequential first-pass metabolism of IMI involves both hydroxylation and demethylation. However, the dose-normalized areas under the serum concentration-time curves indicate that the fractions of the doses converted to metabolites were similar after both routes of IMI administration. Similar total fractions of the i.m. and oral doses recovered in urine indicate complete absorption of the oral doses. Inclusion of the metabolites increased the apparent availability of active components after oral IMI from 22%-50% to 45%-94%. Both the 2-hydroxy metabolites exhibited formation rate-limited kinetics, whereas DMI kinetics were elimination rate-limited. The t1/2 of IMI and 2-hydroxyimipramine (2-OH-IMI) was 6-18 h, while that of DMI and 2- hydroxydesipramine (2-OH-DMI) was 12-36 h. The t1/2 of these compounds was 1.5-2 times longer after the i.m. doses. The metabolite/parent ratios and the disposition of the individual metabolites confirm findings that chronic dosing results in only limited accumulation of hydroxy metabolites.

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

“…The use of in vitro metabolism in scaling to predict human clearance has been a routine practice within pharmaceutical research and development organizations (Obach, 2011). In this study, the predicted CL p of imipramine of 9.4 mL/min/kg from in vitro CL int was consistent with clinical values ranging from 8 to 15 mL/min/kg (Abernethy et al, 1984;Sutfin et al, 1984;Ciraulo et al, 1988;Sallee and Pollock, 1990). The observed CL m of desipramine were 2-3 and 12 mL/min/kg in PM and EM populations, respectively (Brøsen and Gram, 1988;Ciraulo et al, 1988), and, in the present study, CL m of desipramine was reasonably predicted as 1.0 mL/min/kg from in vitro CL int using HLM of PM donors and 6.4 mL/min/kg using EM HLMs.…”

“…Following oral dosing of imipramine to healthy subjects genotyped as CYP2D6 EMs, the desipramine/imipramine AUC ratio was observed to range from 0.48 to 1.1 (Sutfin et al, 1984;Brøsen and Gram, 1988;Kurtz et al, 1997). Both static and dynamic PBPK models successfully provided AUC m /AUC p ratio estimates in reasonable agreement with reported values in EM volunteers.…”

“…For EM populations, the predicted AUC m /AUC p ratios are Sutfin et al (1984) study, in which single intramuscular doses of imipramine were administered to healthy volunteers. b Abernethy et al, 1984;Sutfin et al, 1984;Brøsen et al, 1986;Wells et al, 1986;Skjelbo et al, 1991;Bergstrom et al, 1992;Koyama et al, 1994;Callaghan et al, 1997;Kurtz et al, 1997;Albers et al, 2000. c Brøsen et al, 1986Koyama et al, 1994.…”

Ion Mobility Spectrometry–Mass Spectrometry Analysis for the Site of Aromatic Hydroxylation

“…The actual drift time of the peak for the NMP derivative at 2.55 minutes (Fig. 2D) was 8.21 minutes, suggesting that the major hydroxylated metabolite of imipramine in the incubated sample with human liver microsomes was the 2-hydroxy imipramine 35, which is consistent with both in vitro and clinical data that 2-hydroxylated imipramine (and its glucuronide conjugate in vivo) is a predominant hydroxylated metabolite observed in human liver microsomes (Koyama et al, 1997), plasma, and urine (Sutfin et al, 1984). Further analyses with authentic 2-hydroxyimipramine confirmed the regression line-based metabolite identification by the actual drift time of 8.21 minutes, in excellent agreement with the corresponding calculated value.…”

A comparison of the antinociceptive effects of imipramine, tramadol and anpirtoline [see comments]

“…This protocol was used because peak plasma concentrations of all three drugs are reported to occur at about 2 h after administration [37][38][39]. The drugs were given orally together with 200 ml water (placebo, 60 mg anpirtoline, 150 mg tramadol, and 100 mg imipramine in identical brown capsules).…”