Drug Transport in the Placenta

Mao, Qingcheng; Ganapathy, Vadivel; Unadkat, Jashvant D.

doi:10.1002/9781118705308.ch17

Cited by 5 publications

(3 citation statements)

References 99 publications

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“…Moreover, as the placenta expresses many drug transporters 223 , it is probable that maternal small molecules, of physiological as well as toxicological significance, cross the maternal–fetal barrier in mammals via a set of SLC and ABC transporters. Furthermore, it is at least conceivable that a different set of drug transporters that is transiently expressed in developing tissues can take up and/or extrude these molecules.…”

Section: Figurementioning

confidence: 99%

“…In addition to inter-organ communication, this hypothesis also emphasizes the role of ABC and SLC drug transporters and their close relatives in inter-organismal communication (see the figure, part b ), such as the regulated, drug-transporter-mediated movement of small molecules across the intestine, enabling communication of the body with the gut microbiome 61,159 . These transporters and/or their close relatives also regulate the movement of volatile odorants into the urine, as well as the movement of key metabolites and/or signalling molecules into breast milk or across the placental barrier 7,14,98,112,116,223 . Information, in the form of small molecules that reflect (and affect) cell states and/or tissue physiology, can therefore be transmitted to other cells, organs and/or other organisms of the same or different species via transported substrates (see the figure, part b ).…”

Section: Figurementioning

confidence: 99%

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What do drug transporters really do?

Nigám

2014

Nat Rev Drug Discov

429

529

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Potential drug–drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory concern. However, the endogenous functions of these drug transporters are not well understood. Discussed here is evidence for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. It is suggested that these transporters may be part of a larger system of remote communication (‘remote sensing and signalling’) between cells, organs, body fluid compartments and perhaps even separate organisms. This broader view may help to clarify disease mechanisms, drug–metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury, as well as prenatal and postnatal development.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

What do drug transporters really do?

Nigám

2014

Nat Rev Drug Discov

429

529

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“…The first verification drug, theophylline, is also a Biopharmaceutics Classification System class I drug (Benet, 2010). To date, only OAT2 has been indicated in theophylline tissue uptake, but this transporter is absent in human placenta (Kobayashi et al, 2005;Mao et al, 2014). Theophylline is mainly cleared by CYP1A2 with minor contributions from CYP 3A and CYP2E1 as well as a small renal component (Ke et al, 2013).…”

Section: Our In Vivo Calibrator Midazolam [Biopharmaceutics Classificmentioning

confidence: 99%

Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model II: Verification of the Model for Passive Placental Permeability Drugs

Zhang

Unadkat

2017

Drug Metab Dispos

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Fetal exposure to drugs cannot be readily estimated from single time point cord blood sampling at the time of delivery. Therefore, we developed a physiologically based pharmacokinetic (PBPK) model to estimate fetal drug exposure throughout pregnancy. In this study, we report verification of this novel maternal-fetal PBPK (m-f-PBPK) model for drugs that passively diffuse across the placenta and are not metabolized/transported there. Our recently built m-f-PBPK model was populated with gestational age-dependent changes in maternal drug disposition and maternal-fetal physiology. Using midazolam as an in vivo calibrator, the transplacental passive diffusion clearance of theophylline and zidovudine was first estimated. Then, for verification, the predicted maternal plasma (MP) and umbilical venous (UV) plasma drug concentrations by our m-f-PBPK were compared against those observed at term. Overall, our m-f-PBPK model well predicted the maternal and fetal exposure to the two verification drugs, theophylline and zidovudine, at term, across a range of dosing regimens, with nearly all observed MP and UV plasma drug concentrations falling within the 90% prediction interval [i.e., 5th-95th percentile range of a virtual pregnant population ( = 100)]. Prediction precision and bias of theophylline MP and UV were 14.5% and 12.4%, and 9.4% and 7.5%, respectively. Furthermore, for zidovudine, after the exclusion of one unexpectedly low MP concentration, prediction precision and bias for MP and UV were 50.3% and 30.2, and 28.3% and 15.0%, respectively. This m-f-PBPK should be useful to predict fetal exposure to drugs, throughout pregnancy, for drugs that passively diffuse across the placenta.

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