The Contribution of Lysosomal Trapping in the Uptake of Desipramine and Chloroquine by Different Tissues

Daniel, W.A.; Bickel, Marcel H.; Honegger, Ulrich E.

doi:10.1111/j.1600-0773.1995.tb01050.x

Cited by 55 publications

(42 citation statements)

References 9 publications

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“…Ion trapping was suggested as the main factor for chloroquine accumulation in tissues (48). Very high concentrations were observed in rat kidneys, liver, spleen and lung with a tissue to blood ratio close to 300 (49). A remarkable affinity for melanin in skin and eye (mediated through a charge transfer process) and slow release from the pigmented tissues was suggested (50).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

2015

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-Purpose. The early prediction of pharmacokinetic behavior is of paramount importance for saving time and resources and for increasing the success of new drug candidates. The steady-state volume of distribution (VD ss ) is one of the key pharmacokinetic parameters required for the design of a suitable dosage regimen. The aim of the study is to propose a quantitative structure -pharmacokinetics relationships (QSPkR) for VD ss of basic drugs. Methods: The data set consists of 216 basic drugs, divided to a modeling (n = 180) and external validation set (n = 36). 179 structural and physicochemical descriptors are calculated using validated commercial software. Genetic algorithm, stepwise regression and multiple linear regression are applied for variable selection and model development. The models are validated by internal and external test sets. Results: A number of significant QSPkRs are developed. The most frequently emerged descriptors are used to derive the final consensus model for VD ss with good explanatory (r 2 0.663) and predictive ability (q 2 LOO-CV 0.606 and r 2 pred 0.593). The model reveals clear structural features determining VD ss of basic drugs which are summarized in a short list of criteria for rapid discrimination between drugs with a large and small VD ss . Conclusions: Descriptors like lipophilicity, fraction ionized as a base at pH 7.4, number of cycles and fused aromatic rings, presence of Cl and F atoms contribute positively to VD ss , while polarity and presence of strong electrophiles have a negative effect.

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Section: Discussionmentioning

confidence: 99%

Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

2015

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“…Previous studies with ionophores have used cultured hepatocytes (Lake et al, 1987;Myers et al, 1995) or liver slices (Daniel et al, 1995;Daniel and Wojcikowski, 1999a). Lake et al, (1987) used monensin to characterize the number of acidic compartments in intact hepatocytes (Lake et al, 1987;Myers et al, 1995), and Myers et al (Lake et al, 1987;Myers et al, 1995) applied flow cytometry to make dynamic measurements of the lysosomal pH in living hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Lake et al, (1987) used monensin to characterize the number of acidic compartments in intact hepatocytes (Lake et al, 1987;Myers et al, 1995), and Myers et al (Lake et al, 1987;Myers et al, 1995) applied flow cytometry to make dynamic measurements of the lysosomal pH in living hepatocytes. The studies of Daniel et al (1995) have been focused on the contribution of two factors, nonspecific drug binding to membrane phospholipids and ion-trapping of cationic drugs in tissue slices (Daniel et al, 1995;Daniel and Wojcikowski, 1999a) and the contribution of lysosomal trapping to the total TABLE 1 Non-parametric moments for model cationic drugs (mean Ϯ S.D., n ϭ 6) There were significant differences between controls and treatment groups for the mean transit time of propranolol (** p Ͻ 0.01). No other differences for the non-parametric moment parameters were found between control and treatment groups (p Ͼ 0.05).…”

Section: Discussionmentioning

confidence: 99%

“…The main mechanisms of such a distribution pattern are nonspecific binding to membrane phospholipids (Bickel and Steele, 1974;Francesco and Bickel, 1977;Romer and Bickel, 1979), binding to microsomal protein (Hung et al, 2002), and the sequestration of the compounds into acidic vesicular compartments such as lysosomes or mitochondria (Daniel et al, 1995). A potential consequence of an apparent irreversible sequestration of basic drugs into acidic vesicles is a potentially reduced drug bioavailability (de Duve et al, 1974;Ohkuma and Poole, 1978) or drug interactions (Daniel and Wojcikowski, 1999b;Nebbia et al, 1999).…”

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confidence: 99%

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Ion-Trapping, Microsomal Binding, and Unbound Drug Distribution in the Hepatic Retention of Basic Drugs

Siebert¹,

Hung²,

Chang³

et al. 2003

J Pharmacol Exp Ther

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This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pK a values of drugs. Lipophilicity and pK a determined hepatic drug retention: a drug with low pK a and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pK a and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pK a and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pK a basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.Basic lipophilic compounds are characterized by a high volume of distribution as a result of extensive tissue uptake. The main mechanisms of such a distribution pattern are nonspecific binding to membrane phospholipids (Bickel and Steele, 1974;Francesco and Bickel, 1977;Romer and Bickel, 1979), binding to microsomal protein (Hung et al., 2002), and the sequestration of the compounds into acidic vesicular compartments such as lysosomes or mitochondria (Daniel et al., 1995). A potential consequence of an apparent irreversible sequestration of basic drugs into acidic vesicles is a potentially reduced drug bioavailability (de Duve et al., 1974;Ohkuma and Poole, 1978) or drug interactions (Daniel and Wojcikowski, 1999b;Nebbia et al., 1999). Lysosomal trapping of basic lipophilic drugs has also been demonstrated to be an important determinant of disposition for desipramine and chloroquine and psychotropic compounds such as the piperidine and piperazine-type neuroleptics (Daniel et al., 2001). The lysosomotropic properties of basic drugs are particularly important determining drug disposition and pharmacokinetics in lysosome-rich organs such as lungs, kidneys, or the liver.Specific studies determining the relative contribution of ion-trapping and microsomal binding to the hepatic retention of drugs or relating the relative uptake to the ph...

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“…The experiment was carried out according to the previously developed and described method of Daniel et al (1995). After decapitation, the brain was isolated (the cerebellum and brain stem were discarded) and placed in ice-cold Krebs-Henseleit buer (pH 7.4), saturated with carbogen (95% O 2 /5%CO 2 ) at 378C.…”

Section: Determination Of the Uptake Of Psychotropic Drugs By Tissue mentioning

confidence: 99%

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

Daniel

Wójcikowski

Pałucha

2001

British J Pharmacology

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1 Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its dierent 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 mM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 mM. 3 Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline,¯uoxetine, 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 dierential 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¯uids, may intensify the pharmacological action of the combined drugs.

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The Contribution of Lysosomal Trapping in the Uptake of Desipramine and Chloroquine by Different Tissues

Cited by 55 publications

References 9 publications

Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

Ion-Trapping, Microsomal Binding, and Unbound Drug Distribution in the Hepatic Retention of Basic Drugs

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

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