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PubMed1997

Influence of imipramine on the hypothalamic/pituitary/thyroid axis of the rat.

The effects of the tricyclic antidepressant drug imipramine at different levels of the hypothalamic/pituitary/thyroid axis were investigated in the rat. Intraperitoneal (IP) treatment for 14 days with imipramine at 10 mg/kg, but not 2 mg/kg, reduced serum total thyroxine (T4) and triiodothyronine (T3). A similar decrease in serum total T4 was observed in thyroidectomized T4-treated rats, suggesting that imipramine treatment enhances T4 clearance instead of reducing T4 secretion. There were no parallel decreases in serum free T4 and T3 concentrations, due to the simultaneous increase in the free fractions of both T4 and T3 following imipramine treatment. In vitro experiments using equilibrium dialysis indicated that neither imipramine nor its metabolite desipramine directly influenced the binding of T4 or T3 to their transport proteins following addition to normal serum, suggesting an indirect effect of imipramine or desipramine on free hormone concentrations in vivo. Concentrations of T4 and T3 in the brain, liver, and heart were unaffected by imipramine treatment, suggesting that the drug did not affect cellular uptake and metabolism of T4 and T3. Serum concentrations of thyrotropin (TSH) were unaffected by imipramine pretreatment at either dose level, compatible with the fact that serum free T4 and T3 concentrations were not reduced. Moreover, there was no difference in thyrotrope responsiveness to stimulation by TSH-releasing hormone (TRH) and to inhibition by T4 and T3 in rat anterior pituitary cells cultured ex vivo for 18 hours from control and imipramine-treated rats. Furthermore, in vitro exposure of cultured rat anterior pituitary cells to imipramine and desipramine indicated that both agents decreased TSH secretion only at concentrations greater than 10(-6) mol/L. These concentrations of imipramine and desipramine in the culture medium would exceed the free concentrations of these drugs seen in vivo therapeutically. In addition, no direct effects of 10(-6) mol/L imipramine or desipramine on the TSH response to TRH or to T3 were observed in vitro in cultured pituitary cells. A potential indirect effect of imipramine or desipramine on TSH secretion via altered hypothalamic control of thyrotropes does not seem likely, due to the lack of effect of imipramine treatment on serum TSH concentrations in imipramine-treated rats. In conclusion, imipramine treatment reduces serum total T4 and T3 in the rat, with enhanced clearance being the most likely explanation for the effect on T4. There was no evidence for altered tissue T4 or T3 concentrations or for altered thyrotrope function. The enhanced T4 clearance may explain the reduction in total T4 reported for imipramine-treated depressed patients. However, the effects of imipramine treatment on the transport of thyroid hormones in plasma need to be examined in more detail in patients, since interspecies differences in the nature of the transport proteins preclude extrapolation of the present results from the rat.

Animals↗
PubMed1983

Imipramine metabolites in blood of patients during therapy and after overdose.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.

Adult↗
PubMed1994

Imipramine blocks rapidly activating and delays slowly activating K+ current activation in guinea pig ventricular myocytes.

Imipramine is a tricyclic antidepressant drug that also exhibits antiarrhythmic effects and whose clinical spectrum of activity is similar to that of quinidine. It has been previously demonstrated that imipramine inhibits the aggregate time-dependent outward K+ current (IK). IK is composed of at least two components: a slowly activating La(3+)-resistant delayed rectifying current (IK,s) and a rapidly activating La(3+)-sensitive current (IK,r). To assess the effects of imipramine on IK,r and IK,s, single guinea pig ventricular myocytes were studied using the nystatin-perforated patch-clamp technique in the absence and in the presence of La3+. Imipramine inhibited IK,r and IK,s in a concentration-dependent manner. The effects of imipramine on the aggregate time-dependent outward current were more marked than those on IK,s alone. Thus, 1 mumol/L imipramine decreased the tail currents elicited on return to -30 mV after long depolarizing pulses (5 seconds, from -40 to +50 mV) in the absence and in the presence of La3+ by 27 +/- 4% and 15 +/- 3% (n = 6), respectively. Moreover, the inhibition induced by imipramine was greater after short (0.5-second) pulses than after 5-second depolarizing pulses, both in the absence and in the presence of La3+ (53 +/- 3% and 30 +/- 5%, respectively; n = 6; P < .05). Imipramine did not significantly modify either the activation midpoint or the slope factor of the aggregate IK and IK,s activation curves. The reduction of IK,s by imipramine was voltage dependent and was more marked at negative membrane potentials. In the presence of 1 mumol/L imipramine, the ratio of tail current to time-dependent current remained constant at 0.37 +/- 0.03, regardless of the test pulse duration at +50 mV. Thus, the envelope-of-tails test was satisfied in the presence of 1 mumol/L imipramine, which indicates that imipramine, at this concentration, blocks IK,r. Imipramine (1, 5, and 10 mumol/L) had no effect on the kinetics of the later phase of IK activation but delayed the beginning of the activation of IK,s by 62 +/- 22, 74 +/- 23, and 155 +/- 53 milliseconds in the presence of 1, 5, and 10 mumol/L imipramine, respectively. These results suggest that imipramine preferentially blocks rapidly activating K+ channels. In addition, experiments performed in the presence of 30 mumol/L La3+ suggest that the drug preferentially binds, but maybe not exclusively, to a closed state of the slowly activating K+ channel.

Action Potentials↗
PubMed1988

Parallel pathway interactions in imipramine metabolism in rats.

The in vitro metabolic inhibitions between imipramine and its metabolites were investigated in rat liver microsomes. A type of precursor-metabolite interaction similar to that shown with lidocaine was observed in imipramine metabolism. Desipramine competitively inhibited the formation of 2-hydroxyimipramine from imipramine. Similarly, imipramine inhibited the formation of 2-hydroxydesipramine from desipramine. As in the cases of those 2-hydroxylations, a competitive inhibitory relationship also existed in the N-demethylation pathways of imipramine and 2-hydroxyimipramine. Studies on age-associated alterations of the metabolic rates of imipramine and its metabolites in rats demonstrated that N-demethylation activities of imipramine and of 2-hydroxyimipramine, which showed a large sex difference (male greater than female) in young rats, decreased markedly only in old male rats, while 2-hydroxylation activities of imipramine and desipramine, with no sex difference at any age, did not show a marked alteration in either sex. These data strongly suggest that the hydroxylation pathways of imipramine and desipramine and the demethylation pathways of imipramine and 2-hydroxyimipramine are each sharing the same species of cytochrome P-450. The in vivo metabolic inhibition between imipramine and desipramine was examined by simultaneous intraportal infusion of imipramine (25 nmol/min) and desipramine (175 nmol/min). The steady-state concentration of imipramine after simultaneous infusion was increased twofold over that after infusion of imipramine alone, without any change in the free fraction in blood.

Aging↗
PubMed1986

Effects of combined administration of diazepam and imipramine hydrochloride in rats.

The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50 mg/kg) and/or diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the body weight, organ weights, and activities of various enzymes, including drug metabolizing enzyme systems were investigated in rats during a 15-day period. The plasma concentrations of imipramine and desipramine were also determined. In addition, the effect of a single intravenous administration of imipramine hydrochloride (5 mg/kg) on the plasma concentration-time profiles of imipramine and desipramine was investigated in rats given the same drug treatments. The plasma concentration-time profiles of imipramine and desipramine were analyzed pharmacokinetically. The rats treated with imipramine hydrochloride showed a greater inhibition of body weight gain than those treated with diazepam, and those treated with imipramine hydrochloride and diazepam simultaneously showed a body weight gain similar to those treated with imipramine hydrochloride alone. No significant differences in organ weight (per 100 g of body weight) were found. The imipramine hydrochloride plus diazepam treatment group showed a greater increase in drug-metabolizing enzyme activities than the imipramine hydrochloride treatment group, but the difference was not statistically significant. However, the plasma levels of imipramine and desipramine after oral administration for 15 d suggested that the imipramine hydrochloride plus diazepam treatment group did not show increased imipramine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Drug interactions between imipramine and benzodiazepines in rats.

The concomitant administration of diazepam and imipramine hydrochloride increased desipramine concentration in rat plasma, but decreased 2-hydroxyimipramine and 2-hydroxydesipramine concentrations; the concomitant administration of oxazepam and imipramine hydrochloride decreased imipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine concentrations. Imipramine plasma protein binding was unaltered in all cases. Liver concentrations of imipramine and 2-hydroxydesipramine were increased by concomitant administration of oxazepam and imipramine hydrochloride. Concomitant administration of benzodiazepines and imipramine hydrochloride increased imipramine concentration in the brain. The effects of imipramine hydrochloride on hypothermia induced by reserpine, and on behavioral despair in rats was also studied. The concomitant administration of diazepam and imipramine hydrochloride led to a decrease in the anti-reserpine effect of imipramine hydrochloride and in the imipramine hydrochloride-induced recovery from immobility in the forced swimming test. These results are in accord with the findings on brain concentrations of imipramine and its metabolites.

Animals↗
PubMed1990

Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats.

The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction. Male Wistar rats received imipramine (10 mg/kg i.p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Plasma levels of imipramine and desipramine in man after different routes of administration.

With the object of studying the kinetics of imipramine and desipramine five healthy volunteers received single intramuscular, oral and intravenous doses and multiple oral doses of imipramine hydrochloride on different occasions. Two of the volunteers also received single intramuscular and oral doses of desipramine hydrochloride. Great interindividual differences were noted in the plasma concentrations of imipramine and the formed desipramine after single doses of imipramine hydrochloride. In all subjects more desipramine was formed after oral than after parenteral adminstration of imipramine. The bioavailability of an orally administered dose of imipramine ranged between 29.5 and 54.7%. The concentration of imipramine was generally lower in the blood cells than in the plasma, unlike the concentration of desipramine which was considerably higher in the blood cells. The half-lives of imipramine ranged from 4.0-17.6 hrs (M = 7.6 +/- 2.5) after single oral doses and between 9.2 and 20.2 hrs (M = 14.0 +/- 1.9) after multiple oral doses. The half-lives of the formed desipramine ranged between 13.5 and 61.5 hrs (M = 29.9 +/- 8.7) after multiple oral doses of imipramine hydrochloride. The observed mean steady-state plasma concentration after multiple oral doses of imipramine hydrochloride, 50 mg t.i.d. varied from 21.4-69.0 mug/1 (M = 38.2 +/- 8.7) for imipramine and from 33.7-136.0 mug/1 (M 72.3 +/- 19.5) for desipramine. The great difference in the ability to form desipramine after oral and parenteral administration of imipramine hydrochloride may have therapeutic consequences as imipramine and desipramine have differing pharmacological properties.

Administration, Oral↗