Direct and indirect interactions between antidepressant drugs and CYP2C6 in the rat liver during long-term treatment.

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg i.p.; desipramine, fluoxetine, sertraline at 5mg/kg i.p.; mirtazapine at 3mg/kg i.p.), in the absence of the antidepressants in vitro. Some of the investigated antidepressant drugs added to liver microsomes of control rats inhibited the rate of 7-hydroxylation of warfarin. The obtained K(i) values indicated that nefazodone and fluoxetine were the most potent inhibitors of the studied reaction (K(i)=13 and 23microM, respectively), while tricyclic antidepressants and sertraline were weak in this respect (K(i)=70-127microM). A one-day (i.e. 24h) exposure to fluoxetine and mirtazapine resulted in a significant increase in the rate of the 7-hydroxylation of warfarin in rat liver microsomes. The other studied antidepressants did not significantly affect the rate of the CYP2C6-specific reaction. After two-week treatment with the investigated antidepressants, the increase in CYP2C6 activity observed after 24-h exposure to fluoxetine and mirtazapine was more pronounced. Moreover, unlike after one-day exposure, imipramine and sertraline significantly increased the activity of the enzyme. The other tricyclic antidepressants or nefazodone did not produce any significant effect when administered in vivo. The above-described enhancement of CYP2C6 activity correlated positively with the simultaneously observed increases in the enzyme protein level, which indicates the enzyme induction. The studied antidepressants increased the CYP2C6 protein level in the liver microsomes of rats after chronic treatment: imipramine to 174.6+/-18.3%, fluoxetine to 159.1+/-13.7%, sertraline to 135.3+/-11.2% and mirtazapine to 138.4+/-10.2% of the control. In summary, two different mechanisms of the antidepressant-CYP2C6 interaction have been found to operate in the rat liver: 1) direct inhibition of CYP2C6 shown in vitro mainly for nefazodone and fluoxetine, with their inhibitory effects being somewhat more potent than their action on human CYP2C9; 2) the in vivo induction of CYP2C6 by imipramine, fluoxetine, sertraline and mirtazapine.

The contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazine neuroleptics.

The aim of the present study was to determine optimum conditions for studying promazine and perazine metabolism in rat liver microsomes, and to investigate the influence of specific cytochrome P-450 inhibitors on 5-sulfoxidation and N-demethylation of these neuroleptics. Based on the developed method, the metabolism of neuroleptics in liver microsomes was studied at linear dependence of product formation on time, and protein and substrate concentrations (incubation time: 10 min; concentration of microsomal proteins: promazine-0.7 mg ml(-1), perazine-0.5 mg ml(-1); substrate concentrations: promazine-25, 40 and 75 nmol ml(-1), perazine-20, 35, 50 nmol ml(-1)). A Dixon analysis of the metabolism of neuroleptics showed that quinine (a CYP2D1 inhibitor), metyrapone (a CYP2B1/B2 inhibitor) and alpha-naphthoflavone (a CYP1A1/2 inhibitor) affected, whereas erythromycin (a CYP3A inhibitor) and sulfaphenazole (a CYP2C inhibitor) did not change the neuroleptic biotransformation. N-Demethylation of promazine was competitively inhibited by quinine (K(i)=20 microM) and metyrapone (K(i)=83 microM), while that of perazine-by quinine (K(i)=46.5 microM), metyrapone (K(i)=46 microM) and alpha-naphthoflavone (K(i)=78.8 microM). 5-Sulfoxidation of promazine was inhibited only by quinine (K(i)=28.6 microM), whereas that of perazine-by quinine (K(i)=10 microM) and metyrapone (K(i)=96 microM). The results obtained are compared with our previous findings of analogous experiments concerning thioridazine, and with the data on other phenothiazines and species. In summary, it is proposed that N-demethylation of the mentioned phenothiazine neuroleptics in the rat is catalyzed by the isoenzymes CYP2D1, CYP2B2 and CYP1A2 (CYP1A2 does not refer to promazine). 5-Sulfoxidation of these drugs may be mediated by different isoenzymes, e.g. CYP2D1 (promazine and perazine), CYP2B2 (perazine) and CYP1A2 (thioridazine). Isoenzymes belonging to subfamilies CYP2C and CYP3A do not seem to be involved in the metabolism of the investigated neuroleptics in the rat. The results obtained point to the drug structure and species differences in the contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazines.

The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat.

The aim of this study was to investigate the effect of three selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine and sertraline, on the pharmacokinetics and metabolism of perazine in a steady state in rats. Perazine (10 mg kg(-1), i.p.) was administered twice daily for two weeks, alone or jointly with one of the SSRIs. Concentrations of perazine and its two main metabolites (N-desmethylperazine and 5-sulfoxide) in the plasma and brain were measured 30 min and 6 and 12 h after the last dose of the drugs. Of the investigated SSRIs, fluoxetine and fluvoxamine significantly increased plasma and brain concentrations of perazine (up to 900% and 760% of the control value, respectively), their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in perazine metabolites concentrations and in the perazine/metabolite concentration ratios were observed. Sertraline elevated plasma and brain concentrations of perazine after 30 min. In-vitro studies with liver microsomes of rats treated chronically with perazine, SSRIs ortheir combinations showed decreased concentrations of cytochrome P-450 after perazine and a combination of perazine and fluvoxamine (vs control), and increased concentration after a combination of perazine and fluoxetine (vs perazine-treated group). Prolonged treatment with perazine did not significantly change the rate of its own metabolism. Chronic administration of fluoxetine or sertraline, alone or in a combination with perazine, accelerated perazine N-demethylation (vs control or perazine group, respectively). Fluvoxamine had a similar effect. The 5-sulfoxidation of perazine was accelerated by fluvoxamine and sertraline treatment, but the process was inhibited by administration of a combination of perazine and fluoxetine or fluvoxamine (vs control). Kinetic studies using control liver microsomes, in the absence or presence of SSRIs added in-vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the investigated SSRIs. Sertraline was the most potent inhibitor of perazine N-demethylation but the weakest inhibitor of sulfoxidation. Results of in-vivo and in-vitro studies indicate that the observed interaction between perazine and SSRIs mainly involves competition for an active site of perazine N-demethylase and sulfoxidase. Moreover, increases in the concentrations of both perazine and metabolites measured, produced by the investigated drug combinations in-vivo, suggest simultaneous inhibition of another, yet to be investigated, metabolic pathway of perazine (e.g. aromatic hydroxylation).

Effects of antidepressant drugs on the activity of cytochrome P-450 measured by caffeine oxidation in rat liver microsomes.

Caffeine is a marker drug for testing the activity of CYP1A2 (3-N-demethylation) in humans and rats. Moreover, it is also a relatively specific substrate of CYP3A (8-hydroxylation). In the case of 1-N- and in particular 7-N-demethylation of caffeine, apart from CYP1A2, other cytochrome P-450 isoenzymes play a considerable role. The aim of the present study was to investigate the influence of imipramine, amitriptyline and fluoxetine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that imipramine exerted a most potent inhibitory effect on caffeine metabolism. Imipramine decreased the rate of 3-N-, 1-N- and 7-N-demethylations, and 8-hydroxylation of caffeine, the effect on 3-N-demethylation being most pronounced (Ki = 33 microM). Amitriptyline showed distinct inhibition of 3-N- and 1-N-demethylation of caffeine, though its effect was less potent than in the case of imipramine (Ki = 57 and 61 pM, respectively). The influence of amitriptyline on 8-hydroxylation and especially on 7-N-demethylation of caffeine was weaker (Ki = 108 and 190 pM, respectively) than on 3-N- or 1-N-demethylation, suggesting a narrower spectrum of cytochrome P-450 inhibition by amitriptyline than by imipramine, involving mainly the subfamily CYP1A2, and--to a lesser degree--CYP3A. In contrast to the tested tricyclic antidepressants, fluoxetine did not exert any considerable effect on the 3-N- or 1-N-demethylation of caffeine (Ki = 152 and 196 microM, respectively), which indicates its low affinity for CYP1A2. However, fluoxetine displayed a clear inhibitory effect on caffeine 7-N-demethylation (Ki = 72 microM), the reaction which is catalyzed mainly by other than CYP1A2 isoenzymes. Fluoxetine diminished markedly the 8-hydroxylation of the marker drug; as reflected by Ki values, the potency of inhibition of rat CYP3A by fluoxetine was similar to that of imipramine (Ki = 40 and 45 microM, respectively). In summary, CYP1A2 was distinctly inhibited by imipramine and amitriptyline, CYP3A by imipramine and fluoxetine, while other CYP isoenzymes (CYP2B and/or 2E1) by imipramine and fluoxetine.

Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver.

The primary metabolic pathways of caffeine are 3-N-demethylation to paraxanthine (CYP1A2), 1-N-demethylation to theobromine and 7-N-demethylation to theophylline (CYP1A2 and other enzymes), and 8-hydroxylation to 1,3,7-trimethyluric acid (CYP3A). The aim of the present study was to investigate the influence of phenothiazine neuroleptics (chlorpromazine, levomepromazine, thioridazine, perazine) on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated neuroleptics competitively inhibited caffeine oxidation in the rat liver, though their potency to inhibit particular metabolic pathways was not equal. Levomepromazine exerted the most potent inhibitory effect on caffeine oxidation pathways, the effect on 8-hydroxylation being the most pronounced. This indicates inhibition of CYP 1 A2 (inhibition of 3-N- and 1-N-demethylation; Ki = 36 and 32 microM, respectively), CYP3A2 (inhibition of 8-hydroxylations; Ki = 20 microM), and possibly other CYP isoenzymes (inhibition of 7-N-demethylation; Ki = 58 microM) by the neuroleptics. The potency of inhibition of caffeine oxidation by perazine was similar to levomepromazine. Thioridazine was a weaker inhibitor of caffeine 3-N- and 7-N-demethylation, while chlorpromazine was weaker in inhibiting caffeine 1-N- and 7-N-demethylation, compared to levomepromazine. In summary, the obtained results showed that all the investigated neuroleptics had a broad spectra of CYP inhibition in the rat liver. The isoenzymes CYP1A2 and CYP3A2 were distinctly inhibited by all the investigated neuroleptics, while other CYP isoenzymes (CYP2B and/or 2E1) by perazine and levomepromazine. The CYP3A2 inhibition was most pronounced. (Ki = 20-40 microM).

Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants.

1. Because of serious side-effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2-week treatment) in rats. 2. Imipramine and amitriptyline (5 and 10 mg kg(-1) i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10 mg kg(-1) i.p.) and its metabolites (N-desmethylthioridazine, 2-sulphoxide, 2-sulphone, 5-sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine/metabolite ratios was observed. 3. Imipramine and amitriptyline added to control liver microsomes in vitro inhibited the metabolism of thioridazine via N-demethylation (an increase in K(m)), mono-2-sulphoxidation (an increase in K(m) and a decrease in V(max)) and 5-sulphoxidation (mainly a decrease in V(max)). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism. 4. The varying concentration ratios of antidepressant/thioridazine in vivo appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro. 5. Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P-450 towards 5-sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed in vivo interaction. 6. The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites.

Different effects of amitriptyline and imipramine on the pharmacokinetics and metabolism of perazine in rats.

The aim of this study was to search for possible effects of imipramine and amitriptyline on the pharmacokinetics and metabolism of perazine at steady state in rats. Perazine (10 mg kg(-1), i.p.) was administered to rats twice daily for two weeks, alone or jointly with imipramine or amitriptyline (10 mg kg(-1) i.p.). Concentrations of perazine and its two main metabolites (5-sulphoxide and N-desmethylperazine) in the plasma and brain were measured at 30 min (Cmax), 6h and 12h (slow disposition phase) after the last dose of the drugs. Liver microsomes were prepared 24 h after withdrawal of the drugs. Amitriptyline increased the plasma and brain concentrations of perazine (up to 300% of the control) and N-desmethylperazine, while not affecting those of 5-sulphoxide. Imipramine only tended to increase the neuroleptic concentration in the plasma and brain. Studies with control liver microsomes showed that amitriptyline and imipramine added to the incubation mixture in-vitro, competitively inhibited N-demethylation (Ki (inhibition constant) = 16 microM and 164 microM, respectively) and 5-sulphoxidation (Ki = 57 microM and 86 microM, respectively) of perazine, amitriptyline being a more potent inhibitor of perazine metabolism, especially with respect to N-demethylation. Studies with microsomes of rats treated chronically with perazine or tricyclic antidepressants, or both, did not show significant differences in the rate of perazine metabolism between perazine- and perazine+antidepressant-treated rats. The data obtained were compared with the results of analogous experiments with promazine and thioridazine. It was concluded that elevations of perazine concentration were caused by direct inhibition of the neuroleptic metabolism by the antidepressants. Similar interactions, possibly leading to exacerbation of the pharmacological action of perazine, may be expected in man. Since the interactions between phenothiazines and tricyclic antidepressants may proceed in two directions, reduced doses of both the neuroleptic and the antidepressant are recommended when the drugs are administered jointly.

The influence of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics of thioridazine and its metabolites: in vivo and in vitro studies.

Due to its psychotropic profile, thioridazine is a neuroleptic suitable for a combination with antidepressants in a number of complex psychiatric illnesses. However, because of its serious side-effects, such a combination with selective serotonin reuptake inhibitors (SSRIs) which inhibit cytochrome P-450 may be dangerous. The aim of the present study was to investigate a possible impact of SSRIs on the pharmacokinetics and metabolism of thioridazine in a steady state in rats. Thioridazine (10 mg/kg) was injected intraperitoneally, twice a day, for two weeks, alone or jointly with one of the antidepressants (fluoxetine, fluvoxamine or sertraline). Concentrations of thioridazine and its main metabolites (2-sulfoxide = mesoridazine; 2-sulfone = sulforidazine; 5-sulfoxide = ring sulfoxide and N-desmethylthiorid-azine) were assessed in the blood plasma and brain at 30 min, 6 and 12 h after the last dose of the drugs using an HPLC method. Fluoxetine potently increased (up to 13 times!) the concentrations of thioridazine and its metabolites in the plasma, especially after 6 and 12 h. Moreover, an increase in the sum of concentrations of tioridazine + metabolites and thioridazine/metabolite ratios was observed. In vitro studies with control liver microsomes, as well as with microsomes of rats treated chronically with fluoxetine show that the changes in the thioridazine pharmacokinetics may be attributed to the competitive (N-demethylation, Ki = 23 microM) and mixed inhibition (2- and 5-sulfoxidation, Ki = 60 microM and 34 microM, respectively) of thioridazine metabolism by fluoxetine, and to the adaptive changes produced by chronic administration of fluoxetine, as reflected by inhibition of N-demethylation and formation of sulforidazine. Sertraline seemed to have a tendency to decrease thioridazine concentration in vivo, though in vitro studies showed that - like fluoxetine - it competitively or via mixed mechanism inhibited the three metabolic pathways of thioridazine (Ki = 41 microM, 64 microM and 47 microM, respectively). Chronic treatment with sertraline stimulated thioridazine 2- and 5-sulfoxidation, which may be responsible for the observed tendency of sertraline to decrease concentrations of the neuroleptic. In the case of fluvoxamine, a tendency to increase the thioridazine level was observed, which may be connected with the competitive or mixed inhibition of thioridazine N-demethylation and 2-sulfoxidation by the antidepressant (Ki = 17 microM and 167 microM, respectively). Repeated administration of fluvoxamine did not produce any changes in the activity of thioridazine-metabolizing enzymes. In conclusion, of the SSRIs studied, only fluoxetine produces a substantial increase in the thioridazine level in the plasma and brain. In the case of fluvoxamine, a tendency to increase the thioridazine level should be considered. Coadministration of thioridazine and sertraline seems to be safe, though a tendency to decrease the thioridazine level may be expected.

The influence of selective serotonin reuptake inhibitors on the plasma and brain pharmacokinetics of the simplest phenothiazine neuroleptic promazine in the rat.

The aim of the present study was to investigate a possible impact of the three selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline on the pharmacokinetics of promazine in a steady state in rats. Promazine was administered twice a day for 2 weeks, alone or jointly with one of the antidepressants. Concentrations of promazine and its two main metabolites (N-desmethylpromazine and sulfoxide) in the plasma and brain were measured at 30 min and 6 and 12 h after the last dose of the drugs. All the investigated SSRIs increased the plasma and brain concentrations of promazine up to 300% of the control value, their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in the promazine metabolites' concentrations and in the promazine-metabolite concentration ratios were observed. In vitro studies with liver microsomes of rats treated chronically with promazine, SSRIs or their combination did not show any significant changes in the concentrations of cytochromes P-450 and b-5. However, treatment with fluoxetine, alone or in a combination with promazine, decreased the rates of promazine N-demethylation and sulfoxidation. A similar effect was observed in the case of promazine and fluvoxamine combination. Kinetic studies into promazine metabolism, carried out on control liver microsomes in the absence or presence of SSRIs added in vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the antidepressants. The results of in vivo and in vitro studies indicate the following mechanisms of the observed interactions: (a) competition for an active site of promazine N-demethylase and sulfoxidase; (b) adaptive changes in cytochrome P-450, produced by chronic treatment with fluoxetine or fluvoxamine; (c) additionally, increases in the sum of concentrations of promazine+ metabolites, produced by fluoxetine and sertraline in vivo, suggest simultaneous inhibition of another, not investigated by us, metabolic pathway of promazine, e.g. hydroxylation. In conclusion, all the three SSRIs administered chronically in pharmacological doses, increase the concentrations of promazine in the blood plasma and brain of rats by inhibiting different metabolic pathways of the neuroleptic. Assuming that similar interactions occur in humans, reduced doses of phenotiazines should be considered when one of the above antidepressants is to be given jointly.

Effects of selective cytochrome P-450 inhibitors on the metabolism of thioridazine. In vitro studies.

The aim of the present study was to determine optimum conditions for the study of thioridazine metabolism in rat liver microsomes and to investigate the influence of specific cytochrome P-450 inhibitors on 2- and 5-sulfoxidation, and N-demethylation of thioridazine. Basing on the developed method, the thioridazine metabolism in liver microsomes was studied at linear dependence of the product formation on time, and protein and substrate concentrations (incubation time was 15 min, concentration of microsomal protein was 0.5 mg/ml, substrate concentrations were 25, 50 and 75 nmol/ml). Dixon analysis of tioridazine metabolism carried out in the control liver microsomes, in the absence and presence of specific cytochrome P-450 inhibitors, showed that quinine (CYP2D1 inhibitor), metyrapone (CYP2B1/B2 inhibitor) and alpha-naphthoflavone (CYP1A2 inhibitor) affected while erythromycin (CYP3A inhibitor) and sulfaphenazole (CYP2C9 inhibitor) did not affect the neuroleptic biotransformation. Thus, quinine and metyrapone inhibited competitively thioridazine N-demethylation and mono-2-sulfoxidation. As reflected by Ki values, N-demethylation was inhibited to a higher degree (Ki = 16.5 and 43 microM, respectively) than mono-2-sulfoxidation (Ki = 25 and 137 microM, respectively). On the other hand, alpha-naphthoflavone inhibited competitively not only N-demethylation and mono-2-sulfoxidation, but also 5-sulfoxidation of thioridazine. The calculated Ki values showed that the highest potency of alpha-naphthoflavone to inhibit thioridazine metabolism was observed for N-demethylation and it descended in the following order: N-demethylation (Ki = 13.8 microM) > mono-2-sulfoxidation (Ki = 34 microM) > 5-sulfoxidation (Ki = 70.4 microM). In conclusion, it can be assumed that N-demethylation and mono-2-sulfoxidation are catalyzed by the isoenzymes 2D1, 2B and 1A2 while 5-sulfoxidation only by 1A2; isoenzymes belonging to the subfamilies 2C and 3A seem not to be involved in the metabolism of thioridazine. The obtained results are discussed in the view of species and structure differences in the enzymatic catalysis of phenothiazines' metabolism as well as in relation to their pharmacological and clinical significance.

Pharmacokinetics of phenothiazine neuroleptics after chronic coadministration of carbamazepine.

The aim of the present study was to assess the influence of carbamazepine on the pharmacokinetics of the two phenothiazine neuroleptics thioridazine and perazine in rats. The obtained results are compared with the results of analogical experiments concerning promazine. Thioridazine or perazine (10 mg/kg i.p.) were administered twice a day for two weeks alone or jointly with carbamazepine (15 mg/kg i.p. during the 1st week, and 20 mg/kg i.p. during the 2nd week of treatment). Concentrations of the neuroleptics and their main metabolites in the plasma and brain were measured at 30 min, 6 and 12 h after the last dose of the drugs. Carbamazepine decreased the concentrations of thioridazine and its metabolites (especially mesoridazine and sulforidazine) in plasma at 30 min and 6 h after the last dose of the drugs. Similar changes in the concentrations of thioridazine and its metabolites were observed at 6 h in the brain. Carbamazepine did not significantly influence the pharmacokinetics of perazine. In vitro studies with liver microsomes of control rats revealed that carbamazepine added to the incubation mixture inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its N-demethylation or sulfoxidation by carbamazepine was observed. Neither carbamazepine nor the neuroleptics, administered separately or jointly for two weeks, significantly influenced the concentrations of cytochromes P-450 and b-5 in the liver. Carbamazepine++ given chronically decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine-treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced. In conclusion, carbamazepine given jointly with thioridazine or promazine at pharmacological doses to rats accelerates the metabolism of the neuroleptics, which is not the case with perazine. The observed induction proceeds by metabolic pathways other than N-demethylation or sulfoxidation. The different effect of carbamazepine on the N-demethylation of thioridazine and perazine in liver microsomes of control and carbamazepine-treated rats implicates that the two reactions are not catalyzed by the same enzyme. Such an induction of neuroleptic metabolism by carbamazepine in patients may worsen psychotic symptoms.

Promazine pharmacokinetics during concurrent treatment with tricyclic antidepressants.

The aim of the present study was to search for a possible effect of tricyclic antidepressants on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or an antidepressant (amitriptyline, imipramine) at a dose of 10 mg/kg i.p. twice a day for two weeks. Amitriptyline increased the plasma concentrations of promazine and N-desmethylpromazine. The concentration of promazine sulfoxide was lowered after 30 min, but later it was raised after 6 and 12 h. The interaction was pronounced after 6 and 12 h when the concentration of promazine was 3 times as high, that of N-desmethylpromazine 25 times as high, and that of sulfoxide 22 times as high as those observed after administration of promazine alone. Similar results were obtained in the brain. Imipramine produced less distinct changes in promazine pharmacokinetics. It did not produce any significant changes in promazine concentration (a tendency to raise it after 30 min was observed) in plasma, but it significantly increased the concentration of N-desmethylpromazine and decreased that of promazine sulfoxide. Changes in the brain did not follow closely those in the plasma. In the brain, significant increases in the levels of promazine and its metabolites were observed after 6 and 12 h. In vitro studies with liver microsomes showed that chronic co-administration of the antidepressants did not significantly influence the rate of promazine demethylation and sulfoxidation. Instead, the Lineweaver-Burk's analysis showed that both amitriptyline and imipramine competitively inhibited the two metabolic pathways of the neuroleptic. The potency of imipramine to inhibit the promazine metabolism in vitro was lower than that of amitriptyline, which was in line with its weaker effect on the pharmacokinetics of promazine in vivo. The observed increase in the sum of concentrations of the measured compounds (promazine + metabolites) in the plasma suggests additional inhibition by amitriptyline of another, metabolic pathway of promazine (e.g. hydroxylation). It is concluded that amitriptyline and imipramine which interfere with the metabolism (and probably distribution) of promazine produce potent increases in the brain (in the case of amitriptyline also in the plasma) concentrations of the neuroleptic.

Pharmacokinetics of thioridazine and its metabolites in blood plasma and the brain of rats after acute and chronic treatment.

This study was aimed at investigation of the pharmacokinetics of thioridazine and its metabolites after a single and repeated administrations. Male Wistar rats received thioridazine as a single dose (10 mg/kg i.p.) or they were treated chronically with the neuroleptic (10 mg/kg i.p., twice a day for two weeks). Plasma and brain concentrations of thioridazine and its metabolites (N-desmethylthioridazine, mesoridazine, sulforidazine, and the ring sulfoxide) were determined using the HPLC method. The obtained data showed that sulfoxidation in position 2 of the thiomethyl substituent and in the thiazine ring are main metabolic pathways of thioridazine, and showed that, in contrast to humans, in the rat N-desmethylthioridazine is formed in appreciable amount. The biotransformation of thioridazine was rather fast yielding plasma peak concentrations of metabolites lower than that of the parent compound. The maximum concentrations of thioridazine and its metabolites in the brain appeared later than in plasma. The peak concentrations and AUC values of thioridazine and its metabolites were higher in the brain than in plasma and this corresponded well with their longer half-lives in the brain as compared to plasma. The drug was not taken up by the brain as efficiently as other phenothiazines. Chronic treatment with thioridazine produced significant increases (with the exception of thioridazine ring sulfoxide) in the plasma concentrations of the parent compound and its metabolites which was accompanied with the prolongation of their plasma half-lives. The observed plasma levels of thioridazine were within 'therapeutic range' while the concentrations of its metabolites were relatively lower as compared to those observed in psychiatric patients. The increased plasma concentrations of thioridazine and its metabolites observed in plasma after chronic treatment were not followed by parallel changes in the brain.

Effect of carbamazepine on the pharmacokinetics of promazine.

Combinations of neuroleptics and carbamazepine are administered to psychiatric patients in the therapy of mania, manic-depressive illness and schizophrenia. The present study was aimed at assessing the influence of carbamazepine on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or carbamazepine twice daily for two weeks (promazine, 10 mg/kg ip; carbamazepine, 15 mg/kg ip during the 1st, and 20 mg/kg ip during the 2nd week of treatment). In a short time (1 h) after administration, carbamazepine had a tendency to increase the concentration of promazine in the blood plasma and brain. Lineweaver-Burk's analysis showed that carbamazepine added in vitro competitively inhibited the N-demethylation of promazine in liver microsomes, without affecting the sulphoxidation process. The effect was reflected in vivo (1 h) by an increased promazine/desmethylpromazine ratio. After a long time interval (6 h, 12 h), carbamazepine decreased the concentration of promazine and its metabolites. In vitro studies into the promazine metabolism, conducted on microsomes from rats treated with promazine and/or carbamazepine, did not show acceleration of its demethylation or sulphoxidation by carbamazepine. The obtained results suggest that induction of promazine metabolism by carbamazepine involves metabolic pathways other than N-demethylation or sulphoxidation. It has been concluded that when a phenothiazine neuroleptic, such as promazine, is administered jointly with carbamazepine, a slight increase in the neuroleptic concentration may be expected in a short time after administration, followed by its significant decrease.

The pharmacokinetics of promazine and its metabolites after acute and chronic administration to rats--a comparison with the pharmacokinetics of imipramine.

This study was aimed to investigate the pharmacokinetics of promazine (a phenothiazine analogue of imipramine) after its single and repeated administration. Male Wistar rats received promazine as a single injection (10 mg/kg ip) or they were treated chronically with the neuroleptic, once a day for two weeks. Plasma and brain concentration of promazine, desmethylpromazine and promazine sulphoxide were determined using the HPLC method devised by us. The results of the present study were compared with our earlier data obtained in analogous experiments with imipramine. The obtained data showed that the pharmacokinetics of promazine and imipramine was similar, though certain differences could be noticed. Both those drugs were unevenly distributed throughout the body, occurring in low concentrations in the blood plasma and reaching considerably higher concentrations in the brain. However, the uptake of promazine by the brain was more efficient than that of imipramine. The brain/plasma AUC ratio after a single dose amounted to 28.72 for promazine and 12.78 for imipramine. Their demethylated metabolites behaved in a similar way, where as the level of promazine sulphoxide in the brain was three times lower than that in the plasma. Chronic treatment with promazine or imipramine increased concentrations of the parent compounds and their demethylated metabolites, and prolonged their half-life in the plasma and brain. The plasma level of promazine sulphoxide did not change, and its brain level was decreased by chronic treatment with promazine. The half-life of promazine sulphoxide was prolonged in the plasma but shortened in the brain after repeated administration of promazine. The observed considerable amounts of desmethylpromazine and promazine sulphoxide, formed in vivo, suggest that the two compounds are major metabolites of promazine, and that the metabolic pattern of promazine in the rat and man is similar.

The effect of imipramine on lipid peroxidation in the rat cerebral cortex.

The effect of imipramine (IMI) on lipid peroxidation in the rat cerebral cortex was investigated in ex vivo and in vitro study. It was found that IMI when given to rats chronically (14 x 10 mg/kg ip) but not acutely (10 mg/kg ip), inhibited lipid peroxidation in the cortical membranes of rat brain. When added in different concentrations (0.125-10.0 nmoles/sample) to the cerebral cortical membranes of naive rats in vitro, IMI inhibited lipid peroxidation in concentration-dependent fashion. Using [3H]-IMI it was found that employed procedure for membrane preparation did not removed IMI from cortical membranes of rats treated chronically with the drug and this might explain the lack of antioxidant effect of IMI in animals treated with a single dose of IMI in ex vivo study. A comparative study of IMI and chlorpromazine (CPZ)-whose inhibitory effect on the free radicals formation has been found before-indicated the higher potency of IMI than that of CPZ as radical scavenger in ex vivo and in vitro studies. The results imply that IMI might affect the brain function also through its effect on lipid peroxidation.