Transplacental passage of lamotrigine in a human placental perfusion system in vitro and in maternal and cord blood in vivo
ABSTRACT We studied transplacental passage of lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine; LTG) using an ex vivo human placental perfusion method and in in vivo samples.
Term placentas from healthy mothers without medications were perfused in a recirculating dual perfusion system. LTG (2.5 microg/ml, n=4; 10 microg/ml, n=4) and reference compound antipyrine (100 microg/ml) were added into the maternal circulation. The disappearance of drugs from the maternal circulation and appearance into the foetal circulation was followed every 15 min up to 2 h. Drug concentrations were analysed using high-performance liquid chromatography. In addition to human placental perfusions, we analysed LTG concentrations in maternal vein and cord blood samples after delivery from two epileptic mothers receiving LTG therapy during pregnancy.
LTG was detectable in the foetal circulation at 15 min in all of the perfusions, indicating rapid transfer. Maternal and foetal concentrations reached equilibrium at 60 min with both concentrations used. The feto-maternal ratio was 1.26+/-0.20 with 10 microg/ml LTG and 0.83+/-0.41 with 2.5 microg/ml LTG at the end of the perfusion. The transfer of LTG from the maternal to the foetal compartment at 120 min was 28.9+/-10.7% with 2.5 microg/ml LTG and 37.8+/-3.2% with 10 microg/ml LTG (p>0.05). In the serum samples from epileptic mothers, the cord blood maternal concentration ratio was 1.02 in one pair and 1.55 in the other.
LTG crossed the placenta easily and rapidly, indicating that the maternal treatment leads to a considerable foetal exposure.
- SourceAvailable from: Toivo Halonen
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- "Placentas with macroscopic trauma or significant calcifications were excluded. A dual recirculating perfusion model with separate maternal and fetal circulations , based on the technique developed by Schneider et al. (1972) and Brandes and co-workers (1983), with minor modifications (Pienimäki et al., 1995; Myllynen et al., 2003; Annola et al., 2008; Karttunen et al., 2010) was used. A peripheral artery and a vein of the same chorionic cotyledon were cannulated and the lobe was connected with the fetal circulation in perfusion apparatus. "
ABSTRACT: Many mothers use, against instructions, alcohol during pregnancy. Simultaneously mothers are exposed to a wide range of other environmental chemicals. These chemicals may also harm the developing fetus, because almost all toxic compounds can go through human placenta. Toxicokinetic effects of ethanol on the transfer of other environmental compounds through human placenta have not been studied before. It is known that ethanol has lytic properties and increases the permeability and fluidity of cell membranes. We studied the effects of ethanol on the transfer of three different environmental toxins: nicotine, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and NDMA (N-nitrosodimethylamine) in placental perfusion. We tested in human breast cancer adenocarcinoma cell line MCF-7 whether ethanol affects ABCG2/BCRP, which is also the major transporter in human placenta. We found that the transfer of ethanol is comparable to that of antipyrine, which points to passive diffusion as the transfer mechanism. Unexpectedly, ethanol had no statistically significant effect on the transfer of the other studied compounds. Neither did ethanol inhibit the function of ABCG2/BCRP. These experiments represent only the effects of acute exposure to ethanol and chronic exposure remains to be studied.Toxicology Letters 06/2011; 205(3):257-64. DOI:10.1016/j.toxlet.2011.06.014 · 3.26 Impact Factor
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- "Morphine + Kopecky et al. (1999) Nicotine + Pastrakuljic et al. (1998) Nicotine and cotinine +/+ Sastry et al. (1998) Cocaethylene + Simone et al. (1997) Methadone + Nekhayeva et al. (2005) HIV inhibitors Saquinavir À Forestier et al. (2001) AZT + Olivero et al. (1999) + Boal et al. (1997) Lopinavir/ritonavir + Gavard et al. (2006) Therapeutic agents, antidepressants, antibiotics Amitriptyline + Heikkinen et al. (2001) Trovafloxacin + Casey and Bawdon (2000) Ciprofloxacin, ofloxacin, levofloxacin +/+/+ Polachek et al. (2005) Vancomycin À Hnat et al. (2004) Antidiabetic-related drugs Rosiglitazone À Holmes et al. (2006) Desmopressin À Ray et al. (2004) Glyburide À Nanovskaya et al. (2006) Insulin lispro À Boskovic et al. (2003) À Holcberg et al. (2004) Anaesthetics Lidocaine + la-Kokko et al. (1995) Methohexital + Herman et al. (2000) Ropivacaine and bupivacaine +/+ Johnson et al. (1999) Fentanyl, alfentanil, sufentanil +/+/+ Giroux et al. (1997) Epilepsy drugs Oxcarbazepine and carbamazepine +/À Pienimaki et al. (1997) Lamotrigine + Myllynen et al. (2003) Pregnancy related treatment Hydralazine + Magee and Bawdon (2000) Methimazole and propylthiouracil +/+ Mortimer et al. (1997) Heart condition Digoxin + Schmolling et al. (1997) + indicates a positive transfer and À indicates low or no transfer compared to the reference (e.g. antipyrine). "
ABSTRACT: Pregnant women are daily exposed to a wide selection of foreign substances. Sources are as different as lifestyle factors (smoking, daily care products, alcohol consumption, etc.), maternal medication or occupational/environmental exposures. The placenta provides the link between mother and foetus, and though its main task is to act as a barrier and transport nutrients and oxygen to the foetus, many foreign compounds are transported across the placenta to some degree and may therefore influence the unborn child. Foetal exposures to environmental and medicinal products may have impact on the growth of the foetus (e.g. cigarette smoke) and development of the foetal organs (e.g. methylmercury and thalidomide). The scope of this review is to give insight to the placental anatomy, development and function. Furthermore, the compounds physical properties and the transfer mechanism across the placental barrier are evaluated. In order to determine the actual foetal risk from exposure to a chemical many studies regarding the topic are necessary, including means of transportation, toxicological targets and effects. For this purpose several in vivo and in vitro models including the placental perfusion system are models of choice.Toxicology in Vitro 11/2007; 21(7):1332-40. DOI:10.1016/j.tiv.2007.05.011 · 2.90 Impact Factor
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- "nsport process located at the brain capillary endothelium cells ( Adkison et al . , 1994 ) , suggesting an involvement of Abcc gene encoding multidrug resis - tance protein ( MRP ) in valproate brain transport . It is clear that all the currently used antiepileptic drugs can readily cross placenta ( Kumar et al . , 2000 ; Melchior et al . , 1967 ; Myllynen et al . , 2003 ; Pienimaki et al . , 1995 ; Staud et al . , 1997 ) . To date , there is lack of study for roles of the drug transporter proteins in their transplacental passage or the potential genetic influence of transporter polymor - phisms on their fetal drug exposure . Future studies wiill need to address how to optimize transfer of the AEDs to t"
ABSTRACT: P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins have physiological functions in placental tissue. Several antidepressants, antipsychotics, and anti-epileptic drugs have been found to be substrates of P-glycoprotein and other transporters. The extent that drugs pass through the placental barrier is likely influenced by drug transporters. The rational choice of psychoactive drugs to treat mental illness in women of child-bearing age should incorporate knowledge of both drug disposition as well as expected pharmacologic effects. This review summarizes the current data on drug transporters in the placental passage of medications, with a focus on medications used in clinical psychopharmacology.Drug Metabolism Reviews 02/2007; 39(4):723-46. DOI:10.1080/03602530701690390 · 5.36 Impact Factor