Molecular descriptors that influence the amount of drugs transfer into human breast milk

Agatonović-Kuštrin, Snežana; Ling, Lee Hooi; Tham, Sock Ying; Alany, Raid G.

doi:10.1016/s0731-7085(02)00037-7

Cited by 62 publications

(49 citation statements)

References 133 publications

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“…6). Extrapolating our data to other species, we find that the ciprofloxacin milk/plasma ratio for wild-type mice we measured (3.08 Ϯ 0.92) is close to the value obtained in other species, such as rabbits (3.61) and humans (4.67) (Gardner et al, 1992;Aramayona et al, 1996) and higher than the predicted milk/plasma ratio of 1.5 that physicochemical principles would suggest in human milk (Agatonovic-Kustrin et al, 2002). This value is similar to the ciprofloxacin milk/plasma ratio for Bcrp1 Ϫ/Ϫ mice (1.59 Ϯ 0.08).…”

Section: Discussionsupporting

confidence: 87%

Breast Cancer Resistance Protein (Bcrp/Abcg2) Transports Fluoroquinolone Antibiotics and Affects Their Oral Availability, Pharmacokinetics, and Milk Secretion

Álvarez²,

et al. 2006

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ABSTRACT:The breast cancer resistance protein (BCRP/ABCG2) is an ATPbinding cassette drug efflux transporter that extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds, including their secretion into the milk. The purpose of this study was to determine whether three widely used fluoroquinolone antibiotics (ciprofloxacin, ofloxacin, and norfloxacin) are substrates of Bcrp1/BCRP and to investigate the possible role of this transporter in the in vivo pharmacokinetic profile of these compounds and their secretion into the milk. Using polarized cell lines, we found that ciprofloxacin, ofloxacin, and norfloxacin are transported by mouse Bcrp1 and human BCRP. In vivo pharmacokinetic studies showed that the ciprofloxacin plasma concentration was more than 2-fold increased in Bcrp1 Quinolone antimicrobial drugs are widely used because of their broad spectrum and intense bactericidal activity. They are developed for oral and parenteral use in the treatment of bacterial diseases, including severe systemic infections (Brunner and Zeiler, 1988). Most quinolone antibacterial drugs are rapidly absorbed from the intestine, with a bioavailability of close to 90%, and then penetrate well into most body tissues and fluids. However, some fluoroquinolones have been reported to undergo efflux, which can explain the low bioavailability of some of them; for instance, the bioavailabilities of ciprofloxacin and norfloxacin are 50 to 80% and 30 to 40%, respectively (Sörgel et al., 1989;Lamp et al., 1992). In addition, at least 10% of i.v. administered ciprofloxacin is eliminated by intestinal secretion (Rohwedder et al., 1990). Only 1% of the dose is excreted into the bile (Parry et al., 1988). Some studies indicated that intestinal elimination of ciprofloxacin was not mediated by P-glycoprotein (ABCB1) (Griffiths et al., 1993;Cavet et al., 1997;Dautrey et al., 1999), one of the most important members of the ATP-binding cassette group of transporters, which is often involved in restricting the bioavailability of drugs. Accordingly, several groups (Lowes and Simmons, 2002;Michot et al., 2004) have recently shown that ciprofloxacin is not a substrate of this transporter or of MRP2 (ABCC2), another ABC transporter. However, the pharmacokinetics of ciprofloxacin was suggested to involve one or more active intestinal or hepatobiliary transport mechanisms in rats (Dautrey et al., 1999). Norfloxacin and ofloxacin have also been shown to be subject to active efflux (Cao et al., 1992;Rabbaa et al., 1996). Active secretory mechanisms common to all fluoroquinolones have been suggested (Griffiths et al., 1993(Griffiths et al., , 1994, as well as competition between fluoroquinolones at transporter sites (Rabbaa et al., 1996). However, the precise mechanisms involved in the pharmacokinetics of ciprofloxacin and other fluoroquinolones remain to be clarified.Several adverse effects have been reported with the use of quinolones, including nausea, diar...

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Section: Discussionsupporting

confidence: 87%

Breast Cancer Resistance Protein (Bcrp/Abcg2) Transports Fluoroquinolone Antibiotics and Affects Their Oral Availability, Pharmacokinetics, and Milk Secretion

Álvarez²,

et al. 2006

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“…EH-TBB concentrations were 11-14 times greater and EH-TBB body burdens were 200-300 times greater in whole pup tissue compared with whole fetuses in both low and high dose groups. It is generally accepted that most xenobiotics enter breast milk through passive diffusion from the plasma, and their concentration in the milk depends on their lipophilicity, molecular size, maternal plasma level, protein binding in maternal circulation, half-life, and degree of ionization (Agatonovic-Kustrin et al, 2002). Like EH-TBB (logK OW ¼ 7.73), 2,2 0 ,4,4 0 ,5,5 0 -hexachlorobiphenyl (PCB 153), p,p 0 -dichlorodiphenyldichloroethylene (p,p'-DDE), and hexachlorobenzene (HCB) have logK OW values near 7 and have been shown to be transferred to offspring almost exclusively through milk, rather than by placental transfer (Lyche et al, 2004;Nakashima et al, 1997;You et al, 1999).…”

Section: Brominated Componentsmentioning

confidence: 99%

Editor’s Highlight: Transplacental and Lactational Transfer of Firemaster® 550 Components in Dosed Wistar Rats

Phillips¹,

Chen²,

Rock³

et al. 2016

Toxicol. Sci.

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FiremasterV R 550 (FM 550) is a commercial mixture of organophosphate and brominated flame retardants currently in use as a replacement for pentaBDE. Its organophosphate components include triphenyl phosphate (TPHP) and a suite of isopropylated triarylphosphate isomers (ITPs); its brominated components include 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEH-TEBP). Taken together, these chemicals have been shown to be endocrine disrupting and potentially toxic, and human exposure to them is widespread. In this study, maternal transfer of FM 550 components, and in some cases their metabolites, was investigated in dosed Wistar rats. Gestational and lactational transfer were examined separately, with dams orally exposed to 300 or 1000 mg of FM 550 for 10 consecutive days during gestation (gestational day [GD] 9-18) or lactation (postnatal day [PND] 3-12). Levels of parent compounds were measured in fetus and whole pup tissue homogenates, and in dam and pup serum, and several metabolites were measured in dam and pup urine. EH-TBB body burdens resulting from lactational transfer were approximately 200-to 300-fold higher than those resulting from placental transfer, whereas low levels of BEH-TEBP were transferred during both lactation and gestation. TPHP and ITPs were rapidly metabolized by the dams and were not detected in whole tissue homogenates. However, diphenyl phosphate (DPHP) and mono-isopropylphenyl phenyl phosphate (ip-PPP) were detected in urine from the dosed animals. This study is the first to confirm ip-PPP as a urinary metabolite of ITPs and establish a pharmacokinetic profile of FM 550 in a mammalian model.

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“…[17] A few QSAR models have been constructed to predict M/ P values of drugs. Agatonovic-Kustrin et al [18,19] developed a genetic neural network model using a set of 60 drug compounds and examined a larger set of 123 drugs and applied an artificial neural network to predict their degree of transfer into breast milk. Katritzky et al [7] investigated the prediction of M/P ratios for a set of 115 drugs using multiple linear regression.…”

Section: Ei ð%þ ¼ 100 â ðM=pþ â A=infantdrugclearance ð1þmentioning

confidence: 99%

Prediction of Milk/Plasma Concentration Ratios of Drugs and Environmental Pollutants Using In Silico Tools: Classification and Regression Based QSARs and Pharmacophore Mapping

Kar

Roy

2013

Molecular Informatics

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A large set of 185 compounds with diverse molecular structures and different mechanisms of therapeutic actions was used to develop and validate statistically significant classification and regression based QSTR models for predicting partitioning of drugs/chemicals into breast milk. Pharmacophore mapping was also carried out which showed four important features required for lower risk of secretion into milk: (i) hydrophobic group (HYD), (ii) ring aromatic group (RA), (iii) negative ionizable (NegIon) and (iv) hydrogen bond donor (HBA). QSTR and pharmacophore models were rigorously validated internally as well as externally to check the possibilities of any chance correlation and judge the predictive potential of the models. Pharmacological distribution diagrams (PDDs) were used for the classification model as a visualizing technique for the identification and selection of chemicals with lower partitioning into milk. Our in silico models enable to identify the essential structural attributes and quantify the prime molecular pre-requisites which were chiefly responsible for secretion into milk. The developed models were also implemented to screen milk/plasma partitioning potential for a huge number DrugBank database (http://www.drugbank.ca/) compounds.

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Molecular descriptors that influence the amount of drugs transfer into human breast milk

Cited by 62 publications

References 133 publications

Breast Cancer Resistance Protein (Bcrp/Abcg2) Transports Fluoroquinolone Antibiotics and Affects Their Oral Availability, Pharmacokinetics, and Milk Secretion

Breast Cancer Resistance Protein (Bcrp/Abcg2) Transports Fluoroquinolone Antibiotics and Affects Their Oral Availability, Pharmacokinetics, and Milk Secretion

Editor’s Highlight: Transplacental and Lactational Transfer of Firemaster® 550 Components in Dosed Wistar Rats

Prediction of Milk/Plasma Concentration Ratios of Drugs and Environmental Pollutants Using In Silico Tools: Classification and Regression Based QSARs and Pharmacophore Mapping

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