Characterization of chloroquine plasma protein binding in man.

Walker, O; Birkett, D. J.; Alván, Gunnar; Gustafsson, LL; Sjöqvist, Folke

doi:10.1111/j.1365-2125.1983.tb01513.x

Cited by 52 publications

(31 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such interaction could perturb the membrane structure and cause lysis. However, it is questionable whether this is relevant to physiological conditions, since FP binds to both plasma proteins [37] and erythrocyte cytosolic component(s) [26] with a similar or greater affinity than its binding to phospholipids. Therefore, under physiological conditions, unless FP is present in very large amounts as it is delivered by direct interaction of its protein carrier with the membrane [31], the chances that it would cause membrane damage are very remote.…”

Section: Discussionmentioning

confidence: 99%

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Ginsburg

Demel

1984

Chemistry and Physics of Lipids

View full text Add to dashboard Cite

Hemin, antimalarial drugs and complexes formed between them, have demonstrable effects on biological membranes. Using the phospholipid monolayer model, we show that hemin intercalates into the membrane and increases its surface pressure, depending on the lipid composition and the initial surface pressure: negative surface charges and particularly looser compaction of the phospholipids reduce the effect of hemin. With increasing surface pressure hemin tends to intercalate as a monomer, and the half-saturation concentration of its effect increases exponentially. The antimalarial monovalent drugs quinine and mefloquine, but not chloroquine, also penetrate into the membrane and expand it. All three drugs markedly increase the effect of hemin, but chloroquine reduces the effect in monolayers composed of unsaturated phospholipids. The drugs' effect is mostly due to an increase in the maximal surface pressure and suggests a complexation of heroin and drug within the membrane phase. Preformed hemindrug complexes decrease the half-saturation concentration of the effect and suggest that the complexes adsorb to the membrane, releasing the hemin through an apolar continuum into the phospholipid phase. The implications of the results to the membrane toxicity mechanism proposed for the molecular mode of action of antimalarial drugs are discussed.

show abstract

Section: Discussionmentioning

confidence: 99%

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Ginsburg

Demel

1984

Chemistry and Physics of Lipids

View full text Add to dashboard Cite

show abstract

“…The CQ enantiomers were synthesized (Blaschke etal., 1978 (Walker et al, 1983). The binding of 100 ng ml-I of (±)-, (+)-, (-)-CQ and 10 ng ml-' of DCQ was determined in the plasma from the six volunteers.…”

Section: Methodsmentioning

confidence: 99%

Protein binding of chloroquine enantiomers and desethylchloroquine.

Ofori‐Adjei¹,

Ericsson²,

Lindström³

et al. 1986

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

The protein binding of racemic chloroquine, its enantiomers and desethylchloroquine to plasma, purified human albumin, and al-acid glycoprotein (ao-AGP) was determined by equilibrium dialysis. The binding was not concentration dependent. (+)-Chloroquine bound more to plasma (66.6 ± 1.9%) and albumin (45.9 ± 0.8%) than (-)-chloroquine (48.5 ± 2.4% and 35.3 ± 0.6%, respectively). These differences were statistically significant. (-)-Chloroquine bound more to ot1-AGP (47.5 ± 0.7%) than (+)-chloroquine (34.5 ± 0.5%). The binding of desethylchloroquine to ac-AGP is higher than to albumin (38.9 ± 0.9% and 21.1 ± 0.4%, respectively.

show abstract

“…at ASPET Journals on May 10, 2018 dmd.aspetjournals.org fraction (f u ) in human plasma (0.39; Walker et al, 1983), to predict the in vivo hepatic clearance (CL h ) of CQ using the well stirred model.…”

Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6mentioning

confidence: 99%

IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Projean

Baune²,

Farinotti³

et al. 2003

Drug Metab Dispos

164

117

View full text Add to dashboard Cite

ABSTRACT:In humans, the antimalarial drug chloroquine (CQ) is metabolized into one major metabolite, N-desethylchloroquine (DCQ). Using human liver microsomes (HLM) and recombinant human cytochrome P450 (P450), we performed studies to identify the P450 isoform(s) involved in the N-desethylation of CQ. In HLM incubated with CQ, only DCQ could be detected. Apparent K m and V max values (mean ؎ S.D.) for metabolite formation were 444 ؎ 121 M and 617 ؎ 128 pmol/min/mg protein, respectively. In microsomes from a panel of 16 human livers phenotyped for 10 different P450 isoforms, DCQ formation was highly correlated with testosterone 6␤-hydroxylation (r ‫؍‬ 0.80; p < 0.001), a CYP3A-mediated reaction, and CYP2C8-mediated paclitaxel ␣-hydroxylation (r ‫؍‬ 0.82; p < 0.001). CQ N-desethylation was diminished when coincubated with quercetin (20-40% inhibition), ketoconazole, or troleandomycin (20-30% inhibition) and was strongly inhibited (80% inhibition) by a combination of ketoconazole and quercetin, which further corroborates the contribution of CYP2C8 and CYP3As. Of 10 cDNAexpressed human P450s examined, only CYP1A1, CYP2D6, CYP3A4, and CYP2C8 produced DCQ. CYP2C8 and CYP3A4 constituted low-affinity/high-capacity systems, whereas CYP2D6 was associated with higher affinity but a significantly lower capacity. This property may explain the ability of CQ to inhibit CYP2D6-mediated metabolism in vitro and in vivo. At therapeutically relevant concentrations (ϳ100 M CQ in the liver), CYP2C8, CYP3A4, and, to a much lesser extent, CYP2D6 are expected to account for most of the CQ N-desethylation.

show abstract

Characterization of chloroquine plasma protein binding in man.

Cited by 52 publications

References 4 publications

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Protein binding of chloroquine enantiomers and desethylchloroquine.

IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Contact Info

Product

Resources

About