Johannes Christiansen

Imipramine: clinical effects and pharmacokinetic variability.

Sixty-six hospitalized depressed patients were treated for 4 weeks with imipramine (Tofranil®) 225 mg/day. Blood samples were drawn twice weekly 15 h after the last drug intake, and IP and DMI concentrations in plasma were assayed by quantitative in situ thin-layer chromatography. Clinical rating was carried out once weekly by Hamiltons Rating Scale (HRS), Becks Depression Inventory, WHO Depression Scale (Quantitative Part), and a side-effect scale. The patients were classified on the basis of the WHO Depression Scale (Qualitative Part) as ‘endogenous’ (N=37) or ‘non-endogenous’ depressions (N=29). Antidepressive effect was evaluated on the basis of the posttreatment rating scores.In patients classified as ‘endogenous’ depressions all 12 responding patients (HRS≦7) had plasma levels of IP>45 μg/l and DMI>75 μg/l, whereas 11 out of 14 nonresponding patients (HRS≧16) had plasma levels of one or both compounds below these limits. Ten out of 12 responders had levels of IP+DMI above 240 μg/l, and all nonresponders had levels of IP+DMI below this limit. Patients with partial response (HRS: 8–15) formed an overlapping group. There was no sign of an upper plasma level limit for the antidepressive effect of imipramine.The plasma level/effect relationship was less clear in patients with ‘non-endogenous’ depressions, since several of them responded at low plasma levels.Some relationship between effect on blood pressure (orthostatic effect) and high plasma levels of IP and DMI was found.Using a plasma level limit of IP≷45 μg/l and DMI≷75 μg/l, it was possible to predict the response of the ‘endogenous’ depression group for 10 out of 12 responders and 10 out of 14 nonresponders on the basis of plasma level measurements obtained after 1 week of treatment.

First-pass metabolism of imipramine in man

The systemic availability of orally administered imipramine (IP) varied from 29 to 77% in 4 subjects. The decrease in availability was due to an excess in metabolism after oral administration. This first%pass metabolism did not correlate with plasma half%life, apparent clearance, or the rate of metabolite excretion in urine. There was close correlation with the excess in formation of demethylated metabolites after oral administration, which suggests that the first%pass metabolism is mediated by demethylation, but does not correlate to the total rate of demethylation.

Plasma levels and antidepressive effect of imipramine

The relationship between the antidepressive effect of imipramine and the plasma concentrations of imipramine and the active metabolite desipramine was studied in 24 patients suffering from endogenous depression. After a placebo period of 7 days, the patients received imipramine, 75 mg 3 times a day. The dose was reduced in patients with pronounced side effects. Blood samples for drug assay were drawn in the morning, 15 hr after the last drug intake. Imipramine and desipramine in plasma were assayed by quantitative in situ thin‐layer chromatography. Individual variations in plasma concentration were 20‐ to 30‐fold in both imipramine and desipramine. Severity of depression was assessed on the Hamilton Rating Scale (HRS). Eleven of 12 patients who responded satisfactorily to the treatment (H RS post‐treatment score <8) had plasma concentration of imipramine ≧45 µg/L, and desipramine >75 µg/L, whereas the 12 patients not responding satisfactorily (post‐treatment score on HRS ≧8) all had concentrations of imipramine or desipramine or both below these limits.

INFLUENCE OF PHENOBARBITAL AND DIPHENYLHYDANTOIN ON PLASMA CARBAMAZEPINE LEVELS IN PATIENTS WITH EPILEPSY

A total of 123 patients with epilepsy, trigeminal neuralgia or other pains were treated with carbamazepine, which was given alone in 30, with diphenylhydantoin in 48, with phenobarbital in 18 and in 27 cases all three drugs were given. Carbamazepine was determined by quantitative thin‐layer chromatography with subsequent in situ measurement of fluorescence. The plasma level of carbamazepine was higher when the patients were treated with carbamazepine alone than when they were treated as well with diphenylhydantoin or phenobarbital or with both. The difference was highly significant. Various possible explanations for this difference are discussed.

Cannabis and Alcohol: Effects on Simulated Car Driving

The effects of cannabis and alcohol on simulated car driving were studied. Cannabis resin containing 4 percent Δ1-tetrahydrocannabinol was administered orally in three doses equivalent to 8, 12, and 16 milligrams of that component. Alcohol was given orally in one standard dose of 70 grams. Both cannabis and alcohol increased the time required to brake and start, whereas alcohol increased while cannabis decreased the number of gear changes. An effect of dosage on response was observed with cannabis.

Steady-state kinetics of imipramine in patients.

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 μg/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 μg/l, DMI: 24–659 μg/l and IP+DMI: 58–809 μg/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.

Plasma Concentration and Clinical Effect in Imipramine Treatment of Childhood Enuresis

SummaryThe relationship between steady-state plasma concentration and clinical effect of impramine in the treatment of nocturnal enuresis was studied in 22 hospitalised children. After 1 week on placebo the children were given imipramine in a fixed dose of about 1mg/kg for 3 weeks. The enuresis frequency decreased significantly from the placebo to the first week on imipramine, but then no further improvement was observed.There was a significant correlation between steady-state plasma concentration of desipramine or imipramine + desipramine and the reduction in enuresis frequency during imipramine treatment. The optimum effect was obtained when steady-state levels of imipramine + desipramine were above 60μg/L; i.e. the effective concentration in enuresis is 3 to 4 times lower than in antidepressive therapy.Dose- and weight-corrected, steady-state plasma concentration of imipramine and desipramine were not significantly different from those previously observed in younger adults. In I child, a transient rise in Imipramine and desipramine concentration was seen during a period with fever and bacterial infection.

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 (Vdβ) 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.

Imipramine metabolism in man

Summary1.Radioactive imipramine was administered by mouth to psychiatric patients and metabolites in urine was studied by total counting, extraction and thin layer chromatography.2.Some 40 per cent of the radioactive dose administered appeared in the urine during the first 24 hour period; a total of some 70 per cent during the first 72 hour period.3.Of the administered radioactivity 15 per cent was excreted in the form of non-conjugated metabolites, 35 per cent as conjugated metabolites, 23 per cent as non-extractable.4.Thin layer chromatography showed 4 unknown metabolites containing considerable amounts of radioactivity.

Cannabis metabolites in urine after oral administration

SummaryCannabis was administered to volunteers in a dose of 750 mg which was drunk of a “tea”.Cannabis metabolites were demonstrated in human urine by thin layer chromatography.The demonstration of urinary metabolites after oral administration was dependent on treatment of the urine with β-glucuronidase. No metabolites were demonstrable in urine not treated by enzyme splitting.