Steady-state kinetics of doxepin and imipramine in Saudi patients with interethnic comparison

The pharmacokinetics of doxepin (DX) was studied in 21 Saudi patients treated long term with oral doses of this tricyclic antidepressant agent. The mean (SEM) values of the dose-normalized steady-state concentration and the apparent clearance after oral administration of this drug were 25.8 (4.8) ng·ml^-1/mg·kg^-1 and 2.529 (0.342) l·h^-1·kg^-1, respectively. The pharmacokinetics of impramine (IMI) was also studied in 30 Saudi patients who received oral doses of this drug for long durations. The mean dose-normalized steady-state concentration of IMI was 68.3 (19.7) ng·ml^-1/mg·kg^-1, and the mean apparent clearance after oral administration of IMI was 1.619 (0.353) l·h^-1·kg^-1. The mean (SEM) ratio of the steady-state concentration of the metabolite desipramine (DES) to that of IMI (DES/IMI) was 0.873 (0.151). Using this value and the ratio of the mean apparent clearance after oral administration (TCL) of DES to that of IMI, the fraction of IMI metabolized to DES was calculated to be 0.489. The TCL of DES was estimated from data obtained for three additional patients who received oral doses of this drug for long durations. A mean value of 0.907 (0.351) l·h^-1·kg^-1 was obtained.     

Age alters the observed response of imipramine binding sites to chronic antidepressant treatment in female rats

Age alters hypothalamic imipramine binding sites in female rats. Older females have increased levels of imipramine binding with decreased affinity. The response of hypothalamic imipramine binding sites to chronic antidepressant treatment varies depending on the age of the animals treated. In juvenile female rats imipramine binding sites decrease after antidepressant treatment, consistent with previous reports. However, in young females chronic imipramine treatment produces no change in levels of imipramine binding with a slight decrease in binding affinity. In middle-aged female rats, the same treatment causes an apparent increase in levels of imipramine binding sites along with a decrease in affinity. These decreases in the affinity of imipramine binding sites in older female rats, and the concomitant changes in the levels of imipramine binding are the result of imipramine metabolites remaining in the tissue after antidepressant treatment and interfering with the binding assay, despite extensive washing of the membrane preparation. Thus, the observed changes in the response of imipramine binding sites to chronic imipramine treatment with age are probably due to age-related alterations in the metabolism of imipramine in female rats.     

Pharmacological effects of imipramine and desmethylimipramine in developing rats

Summary Developing rats (newborns, 1-, 2- and 4-weeks old) are significantly less resistant than adults to the toxic action of imipramine. The resistance of 6-weeks old rats does not differ from that of adults.Imipramine and desmethylimipramine (DMI) were effective in counteracting the ptosis and/or the hypothermia produced by reserpine equally in all age groups studied. Atropine was ineffective in this regard.DMI reversed the sedation and hypothermia and counteracted the ptosis induced by benzquinolizine Ro 4-1284 equally in 18–19-days old and adult rats. The characteristic motor hyperactivity induced by the combination of DMI and Ro 4-1284 was pronounced in both 18–19-days old and adults rats.Imipramine lowered the brain noradrenaline level in young and adult rats and counteracted the reserpine-induced depletion of this monoamine.Chlorpromazine slightly lowered the brain noradrenaline level in adult rats but did not influence the reserpine-induced depletion of brain noradrenaline and reserpine syndrome.Preliminary data are reported at the Symposia Role of Mediators in Regulation of Physiological Functions (Kazan, December 1967) and Das depressive Syndrom (West Berlin, February 1968).     

Cerebral pharmacokinetics of imipramine in rats after single and multiple dosages

Summary Pharmacokinetics of imipramine (IMI) and its active metabolite, desipramine (DMI) was studied in rats after administration of a single dose of 10 mg/kg IMI, or after chronic administration of this dose once or twice a day for 14 days. The elimination curves of IMI and DMI from the blood and brain show that both the whole body and the brain behave as multi-compartment systems. Maximum concentrations of IMI and DMI in blood and brain appear at the same time, indicating rapid metabolism of IMI; the concentrations were significantly higher in the brain than in the blood. After the chronic treatment the maximum blood and cerebral levels of IMI and DMI were not much higher than after a single dose, but the elimination was slowed down. Brain concentration of IMI and DMI and brain IMI/DMI concentration ratio do not parallel those in the blood. After a prolonged treatment, once or twice a day, desipramine in the brain is present for the whole period between injections at concentrations sufficient to inhibit the noradrenaline uptake. If the drug is given twice a day, in addition to DMI also IMI is present for the whole time at concentration which may inhibit also serotonin uptake.     

Dose-dependent kinetics of imipramine in elderly patients

In a group of elderly depressed patients treated with imipramine (50–200 mg/day), six patients had the dose changed after 1–3 weeks of treatment. In all cases an increased dose resulted in a considerably disproportional rise in the plasma level of the active metabolite desipramine. In a group of elderly depressed patients treated with nortriptyline (40–100 mg/day) the dose/plasma level ratio could be examined in 6 patients, and there was no tendency towards a disproportional rise in plasma level, when the dose was raised. Dose changes, thus, may result in unpredictable changes in plasma levels during imipramine treatment and therapy control by plasma level monitoring may be difficult in these patients. Additional treatment with perphenazine (8–16 mg/day) to patients on imipramine (N=3) or nortriptyline (N=2) caused a marked rise in drug levels for imipramine in particular affecting the desipramine levels.     

The demethylation of imipramine and clomipramine as apparent from their plasma kinetics

The demetylation of imipramine and clomipramine was studied after administration by different routes of single doses of clomipramine hydrochloride and multiple doses of clomipramine as well as imipramine hydrochloride.Five healthy volunteers received 1 mg of clomipramine hydrochloride/kg body weight as single oral and intramuscular doses on different occasions for the purpose of studying the plasma levels of clomipramine and the desmethylclomipramine formed. Desmethyl-clomipramine was found in the plasma in four of the subjects after oral intake but only in one subject after intramuscular injection. The peak levles of clomipramine were considerably higher after intramuscular than after oral administration. The half-lives of clomipramine after oral administration ranged from 11.6–35.8 h and after intramuscular administration from 20.1–39.6 h .Twenty subjects received either imipramine or clomipramine both orally and intramuscularly during a period of 3 weeks in a crossover design. The plasma levels of imipramine and clomipramine and their demethylated metabolites desipramine and desmethyl-clomipramine were determined during the treatment. The ratio between the plasma level of the parent drug and its demethylated metabolite was on average twice as high during intramuscular as during oral treatment.     

Cerebral and blood pharmacokinetics of imipramine and its active metabolites in the pregnant rat

A single IP dose of imipramine (IMI) was administered to pregnant rats. Whole blood, plasma, and brain concentrations of IMI, desipramine (DMI), and their 2-hydroxylated metabolites were separated by high-pressure liquid chromatography and quantified by fluorescence detection. IMI and DMI rapidly appeared in brain tissue in concentrations greatly exceeding those in whole blood and plasma. The much higher concentration and longer persistence of DMI in brain compared to IMI suggests that the predominant central effects from administered IMI result from biotransformation to DMI. The metabolite: parent area under the curve ratios for the hydroxylated metabolites indicate that their contribution to the pharmacologic effects of IMI and DMI are probably negligible.     

Treatment of experimental imipramine and desipramine poisoning in the rat

The influence of orally administered activated charcoal on organ concentrations of parenteral imipramine and desipramine was investigated. Ancillary distribution experiments indicated that the gastroenteral cycle of these substances might be more important than the enterohepatic cycle. Nevertheless the effectiveness of repeated activated charcoal dosage in lowering antidepressant concentrations in visceral organs is unpredictable. This is interpreted as a consequence of predominant binding of these drugs in the tissues, in contrast to drugs like acetosal and the barbiturates, which are distributed more evenly in the body water. The conclusion is, that activated charcoal has only limited value as an antidotal adsorbent in imipramine or desipramine poisoning.These results were partly communicated at the Spring Meeting of the Deutsche Pharmakologische Gesellschaft in Mainz, March 1974.     

Effect of imipramine and desipramine on the metabolism of serotonin in midbrain raphe stimulated rats

Imipramine, 5 mg/kg, i.p., completely blocked the forebrain 5-HIAA increase in rats that have undergone midbrain raphe stimulation whereas desipramine, 5 mg/kg, i.p., did not. This finding is compatible with the hypothesis that imipramine can block selectively the membrane uptake of serotonin in the central serotoninergic neurons.     

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

Summary 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 administration 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 g/l (M=38.2±8.7) for imipramine and from 33.7–136.0 g/l (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.The results were presented to the Skandinavisk Selskab for Psykofarmakologi (Nagy and Johansson, 1974).     

"Behavioural despair" in rats and mice: strain differences and the effects of imipramine

Rats and mice when forced to swim in a restricted space will rapidly cease attempts to escape and become immobile. Previous experiments have shown that immobility was selectively reduced by antidepressant agents. The present experiments show that important differences exist between strains in both the amount of immobility observed and the effects of imipramine. Strain differences should therefore be taken into account in attempts to replicate results from one laboratory to another.     

Comparison of single dose kinetics of imipramine,nortriptyline and antipyrine in man

The single dose kinetics of imipramine (IP), nortriptyline (NT), and antipyrine (AP) were compared in 7 healthy subjects. Test doses of AP were given intravenously and test doses of IP and NT were given both orally and by intravenous infusion. The plasma concentration/time curves after intravenous IP and NT were analysed according to a 2-compartment open model. In addition a blood flow independent true clearance was calculated according to a sinusoidal perfusion model. Indirect estimates of hepatic blood flow were obtained from the oral and i.v. plasma concentration/time curves after NT administration.Compared to NT, IP had statistically significant higher clearances, shorter half-lives, and smaller apparent volumes of distribution. There was a significant correlation between apparent volume of distribution (Vd) of IP and NT (n=5,r=0.85), but only a weak correlation between the clearance measurements of the two compounds. Systemic clearance of AP and IP showed some positive correlation (n=7,r=0.73), whereas there were no significant correlations between AP and NT kinetics.The data indicate that inter- and intraindividual variations in hepatic blood flow may influence the measurements. Other possible sources of variability are individual differences in hepatic extraction kinetics, and differences in binding to blood constitutents.     

Metabolic interaction between imipramine and carbamazepine in vivo and in vitro in rats

Summary The pharmacokinetic consequences of the combination of carbamazepine with imipramine in male Wistar rats have been investigated. It was found that a 2-week treatment with the combination resulted in the increase of the concentrations of the parent compounds and a simultaneous decrease in their metabolites in blood plasma i.e. carbamazepine inhibited imipramine demethylation in the side chain while imipramine inhibited carbamazepine 10,11-epoxidation. The velocity of imipramine 2-hydroxylation and 10,11-epoxy-carbamazepine hydration did not seem to be changed by the combination. On the basis of studies in vitro it is concluded that the observed metabolic interaction between carbamazepine and imipramine is due to the competition of the drugs for the active centre of cytochrome P 450 and to a certain qualitative alteration of the enzyme by imipramine as can be deducted from the decrease of carbamazepine binding to the cytochrome. Send offprint requests to K. J. Netter     

Thyrotropin releasing hormone: Neurochemical evidence for the potentiation of imipramine effects on the metabolism and uptake of brain catecholamines

Individual differences in the exploratory activity of female hooded rats were measured in a Y-maze on two occasions, 1 week apart, before and after treatment with various tricyclic antidepressant drugs (TAD). Locomotion (maze arm entries), rearing, head-dipping into pots, and, in Experiment II only, sniffing of the pots, were scored for 5 min at each trial. In control (saline-pretreated) rats, individual differences were relatively stable over a 1-week period, as shown by small (r=0.5–0.6) but significant test-retest correlations for activity scores. In Experiment I the main finding was that positive test-retest correlations for entries and rears were abolished by short-term (6 days) pretreatment with imipramine. Also, the amount by which individual scores varied in relation to the mean tended to be reduced after imipramine, although the mean scores were unaffected. Similar effects on entries and rears were produced in Experiment II by giving a single dose of protriptyline before the second test. However, test-retest correlations for head-dipping and sniffing were unaltered, or slightly increased by protriptyline, indicating that the effects on entries and rears were not the result of a nonspecific disruption of behaviour. The effects of chlorimipramine were in contrast to those of imipramine and protriptyline. On the whole, test-retest correlations were unaffected by chlorimipramine, but in the case of Y-maze entries measured before and after short-term pretreatment with the drug, the test-retest correlation was significantly increased. These results are discussed in relation to the blocking action of TAD on the neuronal reuptake of noradrenaline and 5-hydroxytryptamine, and a parallel is drawn between the effects of imipramine and protriptyline on individual differences in animals and the therapeutic effects of these drugs in man.     

Quantitative analysis of the EEG effects produced by imipramine,desipramine, promazine,and monodesmethyl promazine in the isolated perfused rat brain

The effects of imipramine, desipramine, promazine and monodesmethyl promazine on the EEG of the isolated perfused rat brain were studied. The brain preparation was perfused for 30 min with simulated blood, containing of the drugs in a concentration of 10^–5 M. Control experiments were performed without a drug added to the simplified blood. The EEG was recorded at various times on a magnetic tape and was evaluated visually and quantitatively (amplitude and interval histography). The EEG effects of imipramine and promazine as well as the effects of these drugs with their monodesmethyl metabolites were compared. The drugs produced clear EEG changes compared with the control EEG. An increase of the amplitude and a slowing of the frequency were found for all drugs. Only the changes produced by desipramine were not statistically significant. Furthermore, imipramine and promazine provoked grouped spikes, whereas monodesmethyl promazine caused grouped sharp waves; such characteristic patterns could not be observed after desipramine. The pronounced similarity of the EEG effects produced by imipramine and promazine as well as the clear difference between the imipramine and desipramine effects were pointed out as the most striking results. It was suggested that imipramine becomes a typical antidepressant in the whole organism after demethylation.Presented in part at the VIIIth International Congress of Electroencephalography and Clinical Neurophysiology, Marseilles, France, 1973 (Rieger and Krieglstein).This work was supported by a grant from Deutsche Forschungsgemeinschaft. We thank Miss. H. Quallich for epert technical assistance.     

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

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 firstpass 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 t _1/2 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 t _1/2 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.     

Quantification of imipramine and its major metabolites in whole blood,brain, and other tissues of the rat by liquid chromatography

An assay procedure is presented using high-performance liquid chromatography and fluorescence detection for simultaneous determination of imipramine, desipramine, and their 2-hydroxylated metabolites in whole blood and various tissues of the rat. By modifying methods previously described for plasma, we have developed an assay method for sensitive, reproducible quantitation of these compounds in rat plasma, whole blood, brain, liver, and fetus. Increasing the volume of the extraction solvent (20% butanol in hexane) increased recovery of imipramine and desipramine to greater than 90% for all tissues examined. No interfering peaks were observed for any of the tissues studied. Addition of n-butylamine as a modifier to the mobile phase decreased the retention of all four compounds and decreased peak tailing of the demethylated compounds. The total elution time was less than 15 min. Using these methods the coefficient of variation for all four compounds was generally less than 5% for each of the five tissues examined. The calibration curves were linear for standard concentrations of 25–2,000 ng/ml spiked tissue homogenate. This method has sufficient sensitivity and specificity for use in pharmacokinetic studies of imipramine.     

3H-imipramine high-affinity binding sites in rat brain. Effects of imipramine and lithium

The specific high-affinity binding of ³H-imipramine to rat brain membranes was investigated. Five weeks of lithium treatment decreased the number of binding sites, but had no effect on the affinity constants. Long-term imipramine treatment had no effect on the number of binding sites but apparently decreased the affinity. The latter effect was probably due to imipramine remaining in the membrane preparation.     

The effect of chronic administration of antidepressants on the circadian pattern of corticosterone in the rat

Although antidepressant administration has been reported to alter the pituitary–adrenal (PA) axis, the results are puzzling. In the present work, two possible factors contributing to these contradictory results were studied in adult male Sprague–Dawley rats: (i) the type of antidepressant and (ii) the time of day at which samples were taken. Samples were taken under nonstressful conditions. In expt 1, the acute effects of two doses (10 and 20 mg/kg) of the tricyclics clomipramine (CMI), desipramine (DMI) and imipramine (IMI), and the non-specific monoamine oxidase inhibitor (MAOI) phenelzine were studied. Only phenelzine increased plasma corticosterone with the low dose, whereas phenelzine and DMI increased plasma corticosterone with the high doses when measured 30 min after drug administration. In a second experiment, it was observed that after 12 daily doses of the drugs (20 mg/kg), all drugs increased plasma corticosterone at 30 min after the last drug administration. When the circadian pattern of corticosterone was studied in the same experiment, starting on the day after the last drug administration, a significant interaction of drug by time of day was found. Drugs caused changes in the normal levels of plasma corticosterone at certain times and DMI, IMI and phenelzine reduced the number of rats showing the normal corticosterone peak at 1900 hours. No significant effect of drugs on corticosteroid-binding globulin (CBG) was found. In a third experiment, phenelzine and IMI were administered as before, but samples were taken at several times both on the day of the last drug administration and on the following day. The two drugs altered the normal circadian pattern of corticosterone in a somewhat different way, but both caused a reduction of the corticosterone peak at lights off on the day after the last drug administration. The normal relative thymus weight observed in all groups (exp. 2) suggests that the overall biological activity of corticosterone was probably not affected by antidepressants. The present results indicate that most antidepressants are able acutely to activate the PA axis after repeated administration in a similar way or even morestrongly than after the first administration, and that some of these drugs alter normal circadian pattern of corticosterone. No evidence for decreased resting PA activity was found in antidepressant-treated rats. Received: 6 June 1997/Final version: 11 April 1998     

Uptake,subcellular distribution,and transfer processes of imipramine and its metabolites formed in rat liver perfusion systems

Summary Pharmacokinetic processes have been studied using a recirculating rat liver perfusion system. Imipramine and its major metabolites have been determined at various times up to 3 h in perfusate, liver, bile and subcellular liver fractions.Imipramine undergoes a rapid hepatic uptake, the initial extraction being close to 100%. Most of the unchanged drug is then localized in the microsomal fraction. Metabolism is not limited by uptake and follows the pathways known from previous work. Like imipramine, its lipophilic metabolite, desmethylimipramine is bound to microsomes. Its concentration ratios, endoplasmic reticulum/cytosol and liver/perfusate, are around 200. In contrast, the polar glucuronides are easily released from the ER, their site of formation, into the cytosol and presumably from there excreted into the bile. A smaller amount of the glucuronides is increted into the perfusate where they reach a steady state level. Analogous experiments with a non-recirculating perfusion system yielded comparable results except for a more rapid imipramine uptake.The results obtained in this study suggest that the pharmacokinetics of many drugs with high apparent volumes of distribution may be largely governed by intracellular binding of lipophilic compounds and translocation processes of polar metabolites.