Effects of albumin and .ALPHA.1-acid glycoprotein on the transport of imipramine and desipramine through the blood-brain barrier in rats.

Lin, Taichen; Sawada, Yasufumi; Sugiyama, Yuichi; Iga, Tatsuji; Hanano, Manabu

doi:10.1248/cpb.35.294

Cited by 21 publications

(10 citation statements)

References 13 publications

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“…Similar observations were made by Videbaek et al (1999) (Table 2) [67]. De Lange and Danhof [68] collected several papers which describe highly bound drugs (oxicams [69], imipramine and desimirpamine [70], isradipine, darodipine [71]) which also penetrate the BBB in surprisingly high extent ( Table 2). There are several explanations of this phenomenon.…”

Section: The Blood-brain Barriersupporting

confidence: 64%

Biological barriers, and the influence of protein binding on the passage of drugs across them

Wanat

2020

Mol Biol Rep

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Drug-protein binding plays a key role in determining the pharmacokinetics of a drug. The distribution and protein binding ability of a drug changes over a lifetime, and are important considerations during pregnancy and lactation. Although proteins are a significant fraction in plasma composition, they also exist beyond the bloodstream and bind with drugs in the skin, tissues or organs. Protein binding influences the bioavailability and distribution of active compounds, and is a limiting factor in the passage of drugs across biological membranes and barriers: drugs are often unable to cross membranes mainly due to the high molecular mass of the drug-protein complex, thus resulting in the accumulation of the active compounds and a significant reduction of their pharmacological activity. This review describes the consequences of drug-protein binding on drug transport across physiological barriers, whose role is to allow the passage of essential substances-such as nutrients or oxygen, but not of xenobiotics. The placental barrier regulates passage of xenobiotics into a fetus and protects the unborn organism. The blood-brain barrier is the most important barrier in the entire organism and the skin separates the human body from the environment.

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Section: The Blood-brain Barriersupporting

confidence: 64%

Biological barriers, and the influence of protein binding on the passage of drugs across them

Wanat

2020

Mol Biol Rep

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“…It is widely accepted that membrane transport of a drug depends on the free drug concentration in solution. However, because this hypothesis does not fully explain the uptake mechanism for some AGP‐binding drugs, a protein‐mediated uptake system has been proposed [8–11]. In such a system, structural changes in the protein due to interaction with membrane surfaces decrease the drug‐binding capacity.…”

Section: Introductionmentioning

confidence: 99%

Cooperative effect of hydrophobic and electrostatic forces on alcohol‐induced α‐helix formation of α₁‐acid glycoprotein

et al. 2005

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a 1 -Acid glycoprotein (AGP) is a serum glycoprotein that mainly binds basic drugs. Previous reports have shown that AGP converts from a b-sheet to an a-helix upon interaction with biomembranes. In the current studies, we found that alkanols, diols, and halogenols all induce this conformational change. Increased length and bulkiness of the hydrocarbon group and the presence of a halogen atom promoted this conversion, whereas the presence of a hydroxyl group inhibited it. Moreover, the effect was dependent on the hydrophobic and electrostatic properties of the alcohols. These results indicate that, in a membrane environment, hydrophobic and electrostatic factors cooperatively induce the transition of AGP from a b-sheet to an a-helix.

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“…Extraction represents the ratio of the brain uptake clearance to the brain blood flow and was estimated as 81.8%, respectively. The brain extraction of YM992 was similar to other CNS acting drugs, such as diazepam [24], imipramine [20] and midazolam [21]. Thus, the carotid artery injection technique, as well as the integration plot analysis, was useful for the evaluation of the penetration of drugs across the BBB, especially for CNS acting drugs.…”

Section: Discussionmentioning

confidence: 90%

“…The octanol-water partition was revealed to be 40 and the log P value to be 1.4, indicating an intermediate lipophilic property, compared to other CNS acting drugs [20,21].…”

Section: Octanol-water Partitionmentioning

confidence: 99%

Investigation of the high partition of YM992, a novel antidepressant, in rat brain ‐ in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB

Mano¹,

Higuchi²,

Kamimura³

2002

Biopharm & Drug Disp

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Brain extracellular fluid (ECF) concentration of YM992, a novel antidepressant, was determined using brain microdialysis to investigate the high partition of this drug to the brain after systemic administration to rats. Plasma, cerebrospinal fluid (CSF), ECF and brain concentrations were determined at the steady-state after intravenous infusion to rats. The concentration ratio of brain to plasma at the total concentration base was 71.3, while those of ECF to plasma and CSF to plasma at the free concentration base were comparable. The distribution volume in brain was 375 ml/g brain and in vitro binding of YM992 to rat brain was 98.1-98.5%, suggesting a high binding in the brain. The carotid artery injection study showed that the brain uptake index of YM992 was 141%, furthermore, the uptake clearance into brain after i.v. dosing to rats was 0.6 ml/min/g brain, indicating a high permeability at the blood-brain barrier (BBB). These findings suggest that the high partition of YM992 to rat brain is attributed to its high level of binding in the brain as well as its high permeability at the BBB.

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Effects of albumin and .ALPHA.1-acid glycoprotein on the transport of imipramine and desipramine through the blood-brain barrier in rats.

Cited by 21 publications

References 13 publications

Biological barriers, and the influence of protein binding on the passage of drugs across them

Biological barriers, and the influence of protein binding on the passage of drugs across them

Cooperative effect of hydrophobic and electrostatic forces on alcohol‐induced α‐helix formation of α₁‐acid glycoprotein

Investigation of the high partition of YM992, a novel antidepressant, in rat brain ‐ in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB

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Effects of albumin and .ALPHA.1-acid glycoprotein on the transport of imipramine and desipramine through the blood-brain barrier in rats.

Cited by 21 publications

References 13 publications

Biological barriers, and the influence of protein binding on the passage of drugs across them

Biological barriers, and the influence of protein binding on the passage of drugs across them

Cooperative effect of hydrophobic and electrostatic forces on alcohol‐induced α‐helix formation of α1‐acid glycoprotein

Investigation of the high partition of YM992, a novel antidepressant, in rat brain ‐ in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB

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Cooperative effect of hydrophobic and electrostatic forces on alcohol‐induced α‐helix formation of α₁‐acid glycoprotein