Binding of basic and acidic drugs to rat tissue subcellular fractions

Bickel, Marcel H.; Steele, J.W.

doi:10.1016/0009-2797(74)90037-4

Cited by 72 publications

(30 citation statements)

References 30 publications

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“…Only clozapine has been shown to accumulate in the "very low-density lipoprotein" fraction of plasma samples with highly elevated lipoprotein levels, but no such accumulation occurred in standard plasma (Procyshyn et al, 2001). Generally, basic lipophilic compound such as antidepressants, e.g., fluoxetine and imipramine, may bind nonspecifically to membrane phospholipids (Bickel and Steele, 1974;Di Francesco and Bickel, 1977;Romer and Bickel, 1979). Thus, an accumulation of such drugs in phospholipid-rich membrane microdomains such as lipid rafts is highly probable.…”

Section: Discussionmentioning

confidence: 99%

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains

Eisensamer¹,

Uhr²,

Meyr³

et al. 2005

J. Neurosci.

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Section: Discussionmentioning

confidence: 99%

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains

Eisensamer¹,

Uhr²,

Meyr³

et al. 2005

J. Neurosci.

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“…In drug metabolism studies, in vitro systems frequently contain phospholipid membranes, either in assays that use whole cells or assays that use subcellular fractions (e.g., microsomes). Compounds that are lipophilic, and especially those that are also cationic at physiological pH, appear to be able to nonspecifically bind to phospholipid membranes (Bickel and Steele, 1974;Di Francesco and Bickel, 1977;McLure et al, 2000). Such nonspecific binding has been demonstrated to have an effect on measurements of microsomal intrinsic clearance (Obach, 1997(Obach, , 1999 and Michaelis constants for drug metabolism reactions (Venkatakrishnan et al, 2000b;Kalvass et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Impact of Nonspecific Binding to Microsomes and Phospholipid on the Inhibition of Cytochrome P4502D6: Implications for Relating in Vitro Inhibition Data to in Vivo Drug Interactions

Margolis¹,

Obach²

2003

Drug Metab Dispos

128

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The effects of microsomal concentration on the inhibitory potencies of four compounds-fluoxetine, quinidine, imipramine, and ezlopitant-on heterologously expressed recombinant CYP2D6-catalyzed bufuralol 1-hydroxylase activity were determined. Increasing microsomal concentration from 0.0088 to 2.0 mg/ml, using additional microsomes not containing cytochrome P450, resulted in a marked increase in IC 50 and K I values for fluoxetine, ezlopitant, and imipramine, when inhibition constants were calculated using the nominal concentration of inhibitor added to the incubation mixture. The extent of nonspecific binding of these inhibitors to microsomes was determined using equilibrium dialysis. The extent of binding increased with increasing microsomal concentration. Binding was greatest for ezlopitant, followed by fluoxetine, imipramine, and quinidine. Correcting inhibition constants for the extent of nonspecific binding resulted in greater consistency of these values with differing microsomal protein concentrations. This effect was also studied with added phospholipid. Inhibition constants increased with increasing phospholipid, and nonspecific binding was also observed for these four drugs to phospholipid. This suggests that the phospholipid component of microsomes possesses some or all of the responsibility for nonspecific binding, and its effect on inhibitors of drug-metabolizing enzymes. These findings suggest that inhibition constants for drugs as inhibitors of microsomal drug-metabolizing enzymes, such as cytochrome P450, should be corrected for the extent of nonspecific binding to components of the in vitro matrix. The implications of this on the prediction of drug-drug interactions from in vitro data are discussed.

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“…According to this approach, the tissue uptake of the psychotropics studied seems to depend more on the phospholipid binding than on the lysosomal trapping. Studies of Bickel coworkers (Bickel & Steele 1974;Di Francesco & Bickel 1977;Romer & Bickel 1979) showed that the uptake of basic lipophilic drugs in tissue homogenates (in which lysosomes are mostly destroyed) is mainly due to the binding to membrane phospholipids.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Lysosomal Trapping to the Total Tissue Uptake of Psychotropic Drugs

Daniel

Wójcikowski

1997

Pharmacology & Toxicology

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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 pM. 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.

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Binding of basic and acidic drugs to rat tissue subcellular fractions

Cited by 72 publications

References 30 publications

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains

Impact of Nonspecific Binding to Microsomes and Phospholipid on the Inhibition of Cytochrome P4502D6: Implications for Relating in Vitro Inhibition Data to in Vivo Drug Interactions

Contribution of Lysosomal Trapping to the Total Tissue Uptake of Psychotropic Drugs

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Binding of basic and acidic drugs to rat tissue subcellular fractions

Cited by 72 publications

References 30 publications

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT3Receptors in Raft-Like Domains

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT3Receptors in Raft-Like Domains

Impact of Nonspecific Binding to Microsomes and Phospholipid on the Inhibition of Cytochrome P4502D6: Implications for Relating in Vitro Inhibition Data to in Vivo Drug Interactions

Contribution of Lysosomal Trapping to the Total Tissue Uptake of Psychotropic Drugs

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Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains