Effects of protein binding on the placental transfer of propofol in the human dually perfused cotyledon in vitro

He, Yanling; Tsujimoto, Saburo; Tanimoto, Masahiko; Okutani, Ryu; Murakawa, Koh‐ichi; Tashiro, Chikara

doi:10.1093/bja/85.2.281

Cited by 20 publications

(9 citation statements)

References 32 publications

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“…According to Aungst et al who carried out permeability studies of HIV protease inhibitors and other lipophilic drugs, an enhancement in permeability was observed only for the most lipophilic (log P > 3) and highly protein-bound ( > 95%) drugs, such as chlorpromazine, nelfinavir, and DMP 851 [20]. The data in this study is in agreement with literature as the permeability of fenretinide (log P = 8.03; highly protein bound) was enhanced in the presence of BSA, whereas the permeability of antipyrine (log P = 0.39; poor plasma protein binding) [21,22] remained unchanged. However, even at a BSA concentration of 4%, fenretinide exhibited poor permeability (8.8 × 10 −8 cm/sec), which might be due to poor partitioning of the highly lipophilic moiety between the cell membrane and the receiving medium.…”

Section: Permeability Of Fenretinide In the Presence Of Plasma Proteinssupporting

confidence: 89%

Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers

Kokate

Jasti

2006

Invest New Drugs

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Fenretinide is a synthetic retinoid with chemotherapeutic activity against various malignancies. Upon oral administration to animals, fenretinide was found to be incompletely absorbed and excreted primarily in feces. The purpose of this study was to determine the possible reasons for poor oral absorption of fenretinide using Caco-2 cell monolayers. To achieve this purpose, a solid dispersion of fenretinide with Povidone K25 was used. The apparent permeability coefficient (P(app)) of fenretinide across Caco-2 monolayers in the presence of bovine serum albumin (BSA) in the receiver was determined. Apical to basolateral (AP-BL) and basolateral to apical (BL-AP) flux studies were performed to determine the role of an efflux mechanism. In the presence of 4% BSA in the receiver, the P(app) was found to be (8.8 +/- 0.5) x 10(-8) cm/sec. The AP-BL flux increased linearly with an increase in fenretinide concentration (125-640 microM) in the presence of 4% BSA in the receiver. Efflux and paracellular pathways played an insignificant role in the permeability of fenretinide. A significant amount of drug, approximately 13-15% of the initial amount accumulated in the cell membrane. The amount of fenretinide in the donor decreased by 16% over a 3 h period. However, only 0.12% of the initial amount was found in the receiver. Also, the P(app) increased with an increase in plasma protein concentration in the receiver. On the basis of these results, the poor permeability of fenretinide can be attributed to its accumulation in the lipophilic cell membrane and poor partitioning into the receiver medium.

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Section: Permeability Of Fenretinide In the Presence Of Plasma Proteinssupporting

confidence: 89%

Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers

Kokate

Jasti

2006

Invest New Drugs

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“…The use of albumin in the perfusion medium is crucial for the oncotic pressure and microvascular permeability of the placenta 38,39 and for the placental transfer of drugs. Schenker et al 34 and He et al 40 showed with olanzapine and propofol, respectively, the significant effect of protein binding on the degree of transfer. Both of these drugs are extensively bound to plasma proteins, especially to albumin.…”

Section: Discussionmentioning

confidence: 99%

Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta

Heikkinen

Ekblad

Laine

2002

BJOG

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Citalopram, fluoxetine and desmethylfluoxetine all cross the human placenta, and may, therefore, affect the perinatal outcome of infants exposed to these drugs during pregnancy. The transfer of desmethylcitalopram was significantly lower, which in the clinical setting may suggest lower fetal exposure of serotonin re-uptake inhibition by citalopram compared with fluoxetine. The presence of albumin was necessary for the transplacental transfer of both citalopram and fluoxetine.

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“…Schenker et al 34 and He et al 40 showed with olanzapine and propofol, respectively, the significant effect of protein binding on the degree of transfer. Both of these drugs are extensively bound to plasma proteins, especially to albumin.…”

Section: Discussionmentioning

confidence: 99%

Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta

Heikkinen¹

2002

BJOG: An International Journal of Obstetrics and Gynaecology

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Objective To investigate the transplacental transfer and the effects of protein binding on the transfer of citalopram, desmethylcitalopram, fluoxetine and desmethylfluoxetine in the isolated perfused human placenta model. Design Prospective observational study.Methods Fifteen term human placentas were obtained immediately after delivery with maternal consent and a 2-hour non-recirculating perfusion cycle of a single placental cotyledon was set up. Citalopram (1230 nmol/L) and desmethylcitalopram (600 nmol/L) or fluoxetine (1455 nmol/L) and desmethylfluoxetine (1525 nmol/L) were added to the maternal reservoir and their appearance to the fetal circulation was followed by repeated measurements. To investigate the effect of protein binding on the transfer of citalopram and fluoxetine, nine additional perfusions were performed without albumin in the perfusion medium. Citalopram and desmethylcitalopram concentrations were measured by reversed-phase high performance liquid chromatography. Fluoxetine and desmethylfluoxetine concentrations was measured by gas chromatography and antipyrine (used as a reference compound) concentrations spectrophotometrically. Results The mean (SD) steady-state transplacental transfer (TPT SS %) for citalopram, desmethylcitalopram, fluoxetine and desmethylfluoxetine was 9.1%, 5.6% ( P ¼ 0.017 compared with citalopram), 8.7% and 9.1%, respectively, calculated as the ratio between the steady-state concentrations in fetal venous and maternal arterial sides. The TPT SS %s of citalopram, desmethylcitalopram, fluoxetine and desmethylfluoxetine were 86%, 50%, 88% and 91% of that of freely diffusable antipyrine. The absence of albumin significantly reduced the transfer of citalopram and fluoxetine (TPT SS % 1.1% and 4.8%, respectively) but not the transfer of antipyrine. Conclusion Citalopram, fluoxetine and desmethylfluoxetine all cross the human placenta, and may, therefore, affect the perinatal outcome of infants exposed to these drugs during pregnancy. The transfer of desmethylcitalopram was significantly lower, which in the clinical setting may suggest lower fetal exposure of serotonin re-uptake inhibition by citalopram compared with fluoxetine. The presence of albumin was necessary for the transplacental transfer of both citalopram and fluoxetine.

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Effects of protein binding on the placental transfer of propofol in the human dually perfused cotyledon in vitro

Cited by 20 publications

References 32 publications

Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers

Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers

Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta

Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta

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