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W A Daniel

Publications and source records attributed to W A Daniel.

At least 19 recordsLinked to original sources
PubMed2006

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.

Animals↗
PubMed2005

The effect of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and newer antidepressant drugs on the activity and level of rat CYP3A.

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, and desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine and sertraline) and novel antidepressant drugs (mirtazapine and nefazodone) on the activity of CYP3A measured as a rate of testosterone 2beta- and 6beta-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 1 day or 2 weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1) i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in vitro. The investigated antidepressants added to control liver microsomes produced some inhibitory effects on CYP3A activity, which were very weak (most of TADs, K(i)=145-212 microM), modest (clomipramine and sertraline, K(i)=67.5 and 62 microM, respectively) or moderate (nefazodone and fluoxetine, K(i)=42 and 43 microM, respectively). Mirtazapine did not display this kind of properties. One-day exposure of rats to TADs substantially decreased the activity of CYP3A in liver microsomes, which was maintained during chronic treatment. The observed decreases in the enzyme activity were in contrast to the increased CYP3A protein level found after chronic treatment with TADs. On the other hand, sertraline increased the activity of the enzyme after its prolonged administration and its effect correlated positively with the observed elevation in CYP3A protein level. Fluoxetine, mirtazapine and nefazodone did not change the activity of CYP3A in liver microsomes after their administration to rats. Three different mechanisms of the antidepressants-CYP3A interaction are postulated: 1) a direct inhibition of CYP3A by nefazodone, SSRIs and clomipramine, shown in vitro, with the inhibitory effect of nefazodone being the strongest, but weaker than the effects of this drug on human CYP3A4; 2) in vivo inhibition of CYP3A produced by 1 day and maintained during chronic treatment with TADs, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction by sertraline of CYP3A produced only by chronic treatment with the antidepressant, which suggests its influence on the enzyme regulation.

Animals↗
PubMed2005

Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo-possible involvement of different mechanisms.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2D measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (i.p.) for 1-day or 2-weeks (twice a day) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine, perazine 10 mg kg(-1); chlorpromazine 3 mg kg(-1); haloperidol 0.3 mg kg(-1); risperidone 0.1 mg kg(-1); sertindole 0.05 mg kg(-1)), in the absence of the neuroleptics in vitro. Neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2D by competitive or mixed inhibition of the enzyme. Thioridazine (Ki=15 microM) was the most potent inhibitor of the rat CYP2D among the drugs studied, whose effect was more pronounced than that of the other neuroleptics tested: phenothiazines (Ki=18-23 microM), haloperidol (Ki=32 microM), sertindole (Ki=51 microM) or risperidone (Ki=165 microM). The investigated neuroleptics-when given to rats in vivo-also seemed to exert an inhibitory effect on CYP2D via other mechanisms. One-day exposure of rats to the classic neuroleptics decreased the activity of CYP2D in rat liver microsomes. After chronic treatment with the investigated neuroleptics, the decreased CYP2D activity produced by the phenothiazines was still maintained, while that caused by haloperidol diminished. Moreover, risperidone decreased the activity of that enzyme. The obtained results indicate drug- and time-dependent interactions between the investigated neuroleptics and the CYP2D subfamily of rat cytochrome P-450, which may proceed via different mechanisms: (1) competitive or mixed inhibition of CYP2D shown in vitro, the inhibitory effects of phenothiazines being stronger than those of haloperidol or atypical neuroleptics, but weaker than the effects of the respective drugs on human CYP2D6; (2) in vivo inhibition of CYP2D, produced by both 1-day and chronic treatment with phenothiazines, which suggests inactivation of enzyme by intermediate metabolites; (3) in vivo inhibition of CYP2D by risperidone, produced only by chronic treatment with the drug, which suggests its influence on the enzyme regulation.

Animals↗
PubMed2002

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.

Alcohol Oxidoreductases↗
PubMed2001

Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping.

1. Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures. 2. Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of 'lysosomal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na(+)/H(+)-ionophore monensin (10 microM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 microM. 3. Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism. 4. Distribution interactions between antidepressants and neuroleptics took place in neurones via mutual inhibition of lysosomal trapping of drugs. 5. A differential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices. 6. A reduction (via a distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue fluids, may intensify the pharmacological action of the combined drugs.

Amitriptyline↗
PubMed2001

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).

Animals↗
PubMed2000

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.

Amitriptyline↗
PubMed2000

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.

Amitriptyline↗
PubMed1999

The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions.

The purpose of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and tricyclic antidepressants (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline). The experiment was carried out on slices of various rat tissues as a system with intact lysosomes. Thioridazine and antidepressants (5 microM) were incubated separately or jointly with the tissue slices in the absence or presence of "lysosomal inhibitors," i.e., ammonium chloride or monensin. The results show that the contribution of lysosomal trapping to the total tissue uptake of thioridazine is as important as phospholipid binding. A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of substantial distributive interactions between thioridazine and the investigated antidepressants at the level of cellular distribution. Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually decreased their tissue uptake. The potency of antidepressants to decrease thioridazine uptake was similar to that of lysosomal inhibitors. In general, the observed interactions between thioridazine and antidepressants occurred only in those tissues in which thioridazine showed lysosomotropism (the lungs, liver, kidneys, brain, and muscles) but were not observed in the presence of ammonium chloride. The above finding provides evidence that the interactions proceeded at the level of lysosomal trapping. In the adipose tissue and heart no lysosomal trapping of thioridazine was detected and those tissues were not the site of such an interaction. Since the organs and tissues involved in the distributive interactions constitute a major part of the organism and take up most of the total drug in the body, the interactions occurring in them may cause a substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the heart and muscles. An in vivo study into the thioridazine-imipramine interaction showed that joint administration of the drugs under study (10 mg/kg ip) increased drug concentration ratios of lysosome-poor tissue/plasma and lysosome-poor/lysosome-rich tissue. Considering serious side effects of thioridazine and tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the thioridazine-antidepressant combinations studied should be approached with respect to the appropriate dose adjustment.

Amitriptyline↗
PubMed1999

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.

Animals↗
PubMed1999

Lysosomal trapping as an important mechanism involved in the cellular distribution of perazine and in pharmacokinetic interaction with antidepressants.

Perazine, a piperazine-type phenothiazine neuroleptic, is the most frequently chosen drug for combination with antidepressants in the therapy of complex or 'treatment-resistant' psychiatric illnesses. The aim of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of perazine, and the pharmacokinetic interaction between the neuroleptic and antidepressants. Experiments were carried out on slices of different rat organs regarded as a system with functional lysosomes. To distinguish between lysosomal trapping and tissue binding, the experiments were performed in the absence or presence of 'lysosomal inhibitors', i.e. the lysosomotropic compound ammonium chloride or [H+] ionophore monensin, which abolish the pH-gradient of lysosomes. Under steady-state conditions, the highest tissue uptake of perazine was observed for the adipose tissue, which descended in the following order: the adipose tissue>lungs>liver>heart=brain>kidneys>muscles. The contribution of lysosomal trapping to the total tissue uptake amounted to about 40% in the liver, brain and muscles, to 30% in the kidneys, and to 25% in the heart and lungs. In the adipose tissue, no lysosomotropism of perazine was observed. Of the psychotropics studied, perazine was the only drug showing such a high degree of lysosomal trapping in muscles and distinct lysosomotropic properties in the heart. Perazine and the antidepressants used, both tricyclic (imipramine, amitriptyline) and selective serotonin reuptake inhibitors (fluoxetine, sertraline), mutually decreased their tissue uptake. The potency of imipramine to decrease perazine uptake was similar to that of the 'lysosomal inhibitors'. Other antidepressants seemed to exert a somewhat weaker effect. The above interactions between perazine and antidepressants were not observed in the presence of ammonium chloride, which indicates that they proceeded at the level of lysosomal trapping. The adipose tissue in which the drug uptake was not affected by the 'lysosomal inhibitors' was not the site of such an interaction. Ammonium chloride did not affect the drug metabolism in liver slices; other tissues displayed only a negligible biotransformation of the psychotropics studied. A parallel metabolic interaction between perazine and tricyclic antidepressants took part in liver slices (i.e. perazine and antidepressants mutually inhibited their metabolic pathways), but the influence of such an interaction on the lysosomal uptake of the parent compounds in liver slices did not seem to be great. A substantial decrease in concentrations of the drugs in lysosomes (depot form) observed in vitro may lead to an increase in the concentration in vivo of the neuroleptic and antidepressants at the site of action, which, in turn, may increase the risk of cardiotoxic and anticholinergic side-effects of tricyclic antidepressants and sedative and extrapyramidal effects of the neuroleptic.

Ammonium Chloride↗
PubMed1999

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.

Animals↗
PubMed1997

Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs.

The present study was aimed at assessing individual contributions of the phospholipid binding and lysosomal trapping to the total tissue uptake of psychotropic drugs with different chemical structures, such as promazine, imipramine, amitriptyline, fluoxetine, sertraline (basic lipophilic drugs) and carbamazepine (lipophilic, but not basic). We also tried to find out whether lysosomal trapping may be involved in the pharmacokinetic interactions in clinical combinations of psychotropics. Uptake experiments were carried out on slices of various rat tissues as a system with intact lysosomes. Initial concentration of each drug was 5 microM. The results were compared with those obtained in the presence of the "lysosomal inhibitors", ammonium chloride or monensin. The basic lipophilic psychotropics showed high uptake in tissues known for the abundance of lysosomes, mainly the lungs. The highest drug accumulation was found for promazine and amitriptyline. "Lysosomal inhibitors" significantly decreased the uptake of the basic lipophilic drugs, particularly in the lungs and liver. The most potent effect was observed for amitriptyline, imipramine and promazine. The brain showed moderate accumulation of basic lipophilic psychotropics and the effect of the "lysosomal inhibitors" was significant only in the case of amitriptyline, imipramine and sertraline. The only exception to the above regularity were imipramine and sertraline which were taken up more extensively by the adipose tissue than by lysosome-rich tissues such as the lungs or liver. Carbamazepine did not show lysosomotropism. Amitriptyline and promazine mutually decreased their uptake by lung slices when the drugs were incubated jointly. In the presence of ammonium chloride the interaction did not occur. In conclusion, the obtained results show that (1) the lysosomal trapping is an important factor determining the distribution of the basic lipophilic psychotropics; however (2) their tissue uptake depends more on the phospholipid binding than on the lysosomal trapping; (3) the lysosomal trapping may be involved in the pharmacokinetic interactions between psychotropics.

1-Naphthylamine↗
PubMed1997

Interactions between promazine and antidepressants at the level of cellular distribution.

The pharmacokinetic interactions in clinical combinations of a phenothiazine neuroleptic and antidepressants at the level of cellular distribution were investigated. Uptake experiments were performed on slices of various rat tissues as a system with intact lysosomes. Promazine and antidepressants (imipramine, amitriptyline, sertraline, fluoxetine) were incubated separately or jointly with tissue slices for 1 hr. Initial concentration of each drug was 5 microM. The interaction studies were carried out in the absence and presence of ammonium chloride (20 mM), a lysosomotropic compound which increases the internal pH value of lysosomes. All the tissues known for their abundance of lysosomes (the lungs, liver, kidneys) were the site of an interaction between promazine and antidepressants. The neuroleptic and antidepressants mutually inhibited their tissue uptake. The potency of interference of each antidepressant with the lysosomal uptake of promazine was similar. The interactions did not occur in the presence of ammonium chloride, which indicates involvement of the lysosomal trapping. Carbamazepine, a lipophilic but non-lysosomotropic drug, did not interfere with the promazine uptake, and the adipose tissue containing very few lysosomes was never the site of interaction in our experiment. Distribution interactions were also observed in the brain and in some cases in muscles (the tissues less abundant of lysosomes), the effect of the inhibitory drug being usually more potent than that of ammonium chloride. Most of the interactions occurring in these two tissues were also observed in the presence of ammonium chloride. Most of the interactions occurring in these two tissues were also observed in the presence of ammonium chloride, which suggests involvement, at least partially, of a non-lysosomal trapping mechanism. The consequences of the observed distributive interactions at the level of lysosomal trapping in vitro are diminished intralysosomal concentration of the basic lipophilic psychotropic and its increase in cell membranes and fluids. In vivo, a shift from the organs or tissues rich in lysosomes to those less abundant in these organella, and an increase in the free drug concentration in body fluids may be expected. In conclusion, the obtained results show that, regardless of the previously known metabolic interactions between psychotropics, interactions at the levels of cellular and body distribution are also feasible.

1-Naphthylamine↗
PubMed1995

The contribution of lysosomal trapping in the uptake of desipramine and chloroquine by different tissues.

Cationic amphiphilic drugs strongly accumulate in tissues of different organs. Uptake is controlled by two major mechanisms, non-specific binding to membrane phospholipids, and ion-trapping within acidic cellular compartments. The aim of this study was to assess the individual contributions of these two mechanisms on the uptake in vitro of desipramine and chloroquine into tissue slices of control and desipramine-treated rats. Drug uptake into intact slices was compared with uptake into slices with destroyed or non-functional acidic compartments. The sequence of desipramine uptake by tissue slices of eight different organs was: lungs > brain > heart > diaphragm > kidneys > skeletal muscles > adipose tissue > liver. The low desipramine concentration in liver may be due to metabolism of the parent drug by cytochrome P-450. Uptake of chloroquine differed widely between slices of different organs with the sequence: lungs > kidneys = brain = liver > diaphragm = heart = skeletal muscles > adipose tissue. Destruction or inactivation of the acidic compartments by homogenization and freeze-thawing or by ammonium chloride, sodium fluoride, or monensin, reduced drug uptake to similar extents. The reduction was organ-specific and may represent the size of the lysosomal compartment in the respective tissue cells. Uptake of chloroquine was more affected than that of desipramine, suggesting that ion-trapping is the main factor for chloroquine accumulation, while binding to membrane phospholipids, is the main factor for desipramine uptake. Single or multiple-dose treatments of rats with desipramine hardly had any effect on consecutive desipramine uptake into lung and liver slices, while the accumulation of chloroquine was enhanced in these slices. In conclusion, the extent of uptake of cationic amphiphilic drugs into tissue slices was tissue-specific, and the contribution of the two uptake mechanisms was strongly drug-dependent.

Adipose Tissue↗
PubMed1994

Adipose tissue storage of drugs as a function of binding competition. In-vitro studies with distribution dialysis.

Distribution dialysis was used to study binding competition between homogenates of adipose tissue and of lean tissues. The concentration ratios adipose/X (X = blood, muscle, lung, liver) of eight lipophilic drugs were determined in the absence and in the presence of a competing binding system X. With drugs which do not undergo storage in adipose tissue in-vivo, yet have a high volume of distribution, such as imipramine or desipramine, there was strong binding competition, and the balance of distribution was shifted from adipose to lean tissues. In the case of indomethacin with a low volume of distribution this shift was from adipose tissue to blood. With diazepam there was a marked binding competition which was not, however, sufficient to shift the balance of distribution away from adipose tissue. Binding competition was negligible with thiopentone. In contrast, with the equally lipophilic hexethal a moderate binding competition was observed. This is consistent with a decreased adipose tissue storage of the latter barbiturate. It is concluded that binding competition exists not only between blood and tissues but also among individual tissues. It is suggested that occurrence and extent of adipose tissue storage of drugs are determined by binding competition between lean and adipose tissues and, more generally, that distribution of lipophilic drugs is largely a function of binding competition.

Adipose Tissue↗
PubMed1986

Chronic chest pain in children and adolescents.

Chest pain is a common symptom of older children and adolescents. The majority of the conditions causing it are benign and self-limiting. Almost all diagnoses can be made with a thorough history and physical examination. Most important, the patient and parents need to be assured that there is no heart defect and that there is no imminent danger of dying.

Adolescent↗
PubMed1986

Hyperventilation syndrome.

Hyperventilation is a common, though often unrecognized, disorder of adolescents. While relatively benign, the lack of recognition may lead to extensive, expensive, and unnecessary medical work-ups. The single most important factor in making the diagnosis of HVS lies in the awareness of the disorder's existence. HVS may be diagnosed through a positive response to the provocation test. Patients are asked to hyperventilate and questioned as to whether they experience the symptoms of which they have complained. Successful treatment involves reassurance, education, and giving the patient a strategy for controlling the hyperventilation. If treatment is not successful in a short period, patients should be referred to a qualified mental health professional. While the relationship between hyperventilation and anxiety disorders is unclear, some correlation between them does appear to exist.

Adolescent↗