ARTICLE IN PRESS Placenta (2005), jj, jjjejjj doi:10.1016/j.placenta.2005.09.001 Designing Pregnancy Centered Medications: Drugs Which Do Not Cross the Human Placenta* C. Gedeon1 and G. Koren2,* Division of Clinical Pharmacology Toxicology, Hospital for Sick Children and University of Toronto, Canada Paper accepted 10 September 2005 This review considers and evaluates the role of placental transporters (multidrug resistance proteins, P-glycoprotein and breast cancer resistance protein) in the uptake and efflux of drugs used in pregnancy. The effect of placental transporters in effluxing drugs such as glyburide and numerous protease inhibitors from the fetal circulation offers the potential to manipulate the passage of drugs across the placenta. The discovery of the interactions of these drugs with placental transporters may provide a novel framework for future drug development in which medications can be designed to control the degree of fetal exposure and thus prevent fetal risk. Placenta (2005), jj, jjjejjj Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Human placenta; ABC transporters; Glyburide; Protease and reverse transcriptase inhibitors A large number of pregnant women suffer from medical conditions that require ongoing or episodic drug treatment such as asthma, epilepsy or hypertension. Moreover, pregnancy can induce conditions such as nausea and vomiting which may need to be treated. Pharmacologically, while the woman’s well being is at the heart of any medical treatment, placental transfer of drugs leading to potential toxicity to the fetus is a major concern in the pharmacological management of the pregnant patient. Hence, when managing a pregnant patient with medication, the treatment of 2 individual patients, mother and fetus should be considered independently, and the decision must be based on the risk/benefit assessment of both. While the use of prescription drugs has sometimes increased fetal risk of teratogenicity, some medical conditions such as gestational diabetes, hyperthyroidism or hypertension may require drug therapy in order to ensure optimal health of the mother and fetus. Of the thousands of available drugs, relatively few have been shown to adversely affect the fetus. For example, the use of most traditional anti-convulsants, while necessary for the treatment of mother, may cause structural defects as well as impaired neurocognitive development [27,28]. Thus, a potential maternalefetal conflict brings to light the need to identify * Supported by a grant by the Canadian Institute for Health research. * Corresponding author. Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: þ1 416 813 5180. E-mail address: [email protected] (G. Koren). 1 C. Gedeon is supported by a studentship by the Ontario Graduate Scholarship. 2 G. Koren holds the Ivey Chair in Molecular Toxicology at the University of Western Ontario. 0143e4004/$esee front matter drugs that can effectively treat the mother without adversely affecting the fetus. Placental passage of a drug is a function of multiple factors such as protein binding, lipid solubility and ionization constant (pKa), but fetal exposure to drugs also depends on maternal pharmacokinetics including the volume of distribution, the rate of metabolism and excretion by the placenta, the pH difference between maternal and fetal fluids, and the effect of haemodynamic changes in the mother during pregnancy (Table 1). Ideally, one may wish to identify drugs that will not cross the placental barrier. However, with the exception of drugs with large molecular weights, such as heparin or insulin, most drugs appear to cross the placenta and are associated with varying degrees of fetal exposure. Recently we have been witnessing a pharmacological breakthrough: glibenclamide (GlyburideÒ), a drug used to treat gestational diabetes, does not appear to demonstrate significant maternal to fetal transfer. In vitro, studies by Elliott et al.  have demonstrated negligible levels of glibenclamide in the fetal compartment even when maternal concentrations were 8 times greater than therapeutic concentrations. Glibenclamide’s poor maternal to fetal transfer may be due to its high protein binding (99.8%), its short elimination half-life (6 h) and importantly the role of specific placental transporters such as P-glycoprotein (P-gP), multidrug resistance protein 1 (MRP1), multidrug resistance protein 2 (MRP2) or multidrug resistance protein 3 (MRP3) [24,25]. Indeed, in a recent placental perfusion study, we have documented that glibenclamide is transferred from the fetal to the maternal circulation against its concentration gradient. This may be the first generation of drugs on the journey Ó 2005 Elsevier Ltd. All rights reserved. ARTICLE IN PRESS Placenta (2005), Vol. jj 2 Table 1. Physiological changes in pregnancy Function Change Cardiac output Tidal volume Pulmonary blood flow Gastric pH Glomerular filtration rate Renal drug elimination Hepatic drug elimination Clearance Total body water Volume of distribution Steady state plasma concentration Peak serum concentration Intestinal motility Protein binding capacity Increased Increased Increased Increased Increased Increased Increase, decrease or unchanged Increased Increased Increased Decreased Decreased Decreased Decreased raised areas denoted as maternal lobes or cotyledons. Each maternal cotyledon is associated with several fetal cotyledons allowing for maternal circulation to be nearly superimposed on to fetal circulation. Considering the movement of materials from the mother to the fetus, molecules are carried by the maternal bloodstream in 1 of 3 ways: in free form dissolved in plasma, bound to carrier proteins, or bound to red blood cells. As a molecule crosses from the maternal to the fetal bloodstream, the solutes must cross the syncytiotrophoblast either by passing through the cytoplasm of the trophoblast or via a network of transporters (Figure 1). Thus, transport across the placenta involves the movement of molecules between 3 compartments: the maternal blood, the cytoplasm of the syncytiotrophoblast and the fetal blood. Solute levels in each of these compartments will play a key role in controlling the rate by which substances cross the placenta and are largely dependent on the initial absorption of the drug into maternal bloodstream. Source [21,28]. PHYSIOLOGICAL CHANGES IN PREGNANCY towards an ideal drug specifically designed for pregnancy. The objective of this conceptual paper is to identify the characteristics that render drugs capable of staying in maternal circulation while obviating fetal exposure and risk, making them optimal for use in pregnancy. TRANSPLACENTAL TRANSPORT MECHANISMS Typically discoid, the human placenta consists of the chorionic villi having attendant blood vessels and connective tissues. Viewed from the basal surface, the placenta displays slightly Maternal compartment D P B R U S H B O R D E R During pregnancy, the maternal gastrointestinal absorption of drugs may be altered because of changes in gastric secretion and motility. Changes in gastric pH influence the degree of ionization and solubility of many drugs, where their absorption rate is modified thereby altering drug bioavailability. Once absorbed, maternal drug metabolism may be altered due to elevation of endogenous hormones such as progesterone. This can stimulate the hepatic microsomal oxidase system where elevated rates of hepatic metabolism may result in increased transformation of drugs such as phenytoin [27,28]. Conversely, theophyline and caffeine experience reduced hepatic elimination as Fetal compartment Facilitated or passive Diffusion MRP 1 D MRP2 Active transporters RBC MRP 3 D BCRP P-gP B A S O L A T E R A L Figure 1. Transport across the placental barrier. Drug bound to protein Drug bound to RBC Free drug ARTICLE IN PRESS Gedeon, Koren: Designing Pregnancy Centred Medications 3 a consequence of elevated estradiol, which may inhibit microsomal drug metabolizing enzymes. Therapeutic concentrations of the active drug may also be affected by haemodynamic changes that take place throughout pregnancy. Cardiac output and blood volume increase by 40% primarily due to an increase in plasma volume . Total body water also increases by 5e8%, due to the expansion of the extracellular fluid space and the growth of new tissue [27,28]. Body water also accumulates in the fetus, placenta and amniotic fluid, which collectively contributes to an increase in volume of distribution and may lower the concentration of drugs and increase their elimination half-life (Table 2). PROTEIN BINDING IN PREGNANCY Protein binding alterations may also occur in pregnancy as a result of changes in the concentration of specific proteins as well as changes in protein binding affinity. Decreases in maternal serum albumin may lead to corresponding increases in the free fraction of drug [4,7]. Increased levels of free fatty acids and total lipids together with the hormonal changes in pregnancy can also decrease the binding capacity of drugs to protein. This may have important implications to maternalefetal drug transfer, since binding changes may influence the maternal plasma concentration of free drug available to partition across the placental barrier. Furthermore, there is a lower concentration of specific binding proteins and altered binding affinity of drugs in the fetus: albumin concentration in the cord blood of neonates is markedly lower than the maternal levels . In addition, there is a 3 fold lower level of a1-acid glycoprotein in the fetus compared to the mother . Should free drug cross the placenta, the fetus will experience larger concentrations of the free drug, due to its diminished protein binding capacity. also influence the passage of the drug across the placenta. In general, uncharged, un-ionized molecules with high lipid solubility and lower molecular weight penetrate the cell membranes more readily than hydrophillic ionized drug molecules . The transfer of weak acids and bases is influenced by the pH gradient between the maternal and fetal circulations and by the pKa of the drug. Since fetal plasma is slightly more acidic, 0.1 lower than maternal plasma pH, for weak bases, the un-ionized free drug crossing the placenta becomes ionized and is ‘trapped’ in the more acidic fetal circulation [22,27]. The pH of the amniotic fluid is also lower than that of maternal plasma. Therefore, the more acidic environment of both fetal blood and amniotic fluid favor ionization and accumulation of basic drug due to ‘‘ion trapping’’ often resulting in fetal drug concentrations that may exceed maternal plasma concentrations and lead to toxicity. Finally, at the placental cytoplasmic barrier, free drug can cross either by simple or facilitated diffusion or by active transport. Diffusion, simple or facilitated, depends upon the transmembrane concentration gradient, where it moves from a higher concentration compartment to an area of lower concentration. Active transport depends not only on solute concentration but also on a steady supply of ATP. In addition, the placenta itself contributes to maternalefetal drug transfer since it possesses metabolizing enzymes capable of oxidation, reduction, hydrolysis and conjugation which can potentially convert an inactive drug into an active metabolite and vice versa. Clearly, the transfer of drugs across the placental membrane will vary, depending on the apparent volume of distribution, the degree of protein binding, acidebase equilibrium, metabolic and excretory mechanisms in the placenta and fetus as well as haemodynamic alterations. GESTATIONAL pH CHANGES GLUCOSE, HYPERGLYCEMIA AND GESTATIONAL DIABETES Lipid solubility, the pH of the maternal and fetal fluids, the ionization constant of the drug (pKa) and the molecular weight Many active transporters mediate the absorption, metabolism and excretion of drugs in the mammalian body, and are largely Table 2. Pregnancy induced pharmacokinetic changes for selected drugs T½ Drugs Ampicillin Cefuroxime Imipenem Piperacillin Azlocillin Nifedipine Labetolol Sotalol Phenytoin Vd (l) CL (ml/min) Pregnant Non-pregnant (min) Pregnant Non-pregnant (min) Pregnant Non-pregnant 54.2 3.9 44 5 36 8 46.5 10 65.4 81 18 102 16 396 36 900 314 69.6 6.1 58 8 41 16 53.7 4.6 72 360 160 558 42 32.8 2.5 17.8 1.9 47.1 14.8 67.6 11.8 15.4 34.5 2.7 16.3 2.1 18.9 5.8 41.9 6.2 24.7 450 31 282 34 973 47 1538 362 126.1 266 105 1704 531 196 24 370 30 198 27 338 85 540 75 195.7 27 15 1430 109 7 Source: [32,34e37]. 106.4 8.1 87.3 7.2 ARTICLE IN PRESS 4 Placenta (2005), Vol. jj GLIBENCLAMIDE: BREAKTHROUGH TREATMENT FOR GESTATIONAL DIABETES dependent on ATP, rendering glucose and its metabolism of particular importance to transplacental transport. In particular, glucose uptake and transfer show a marked dependence on maternal plasma glucose levels. Forty percent of total glucose taken up by the placenta is subsequently transferred to the fetal circulation . Particularly, insulin is an important regulator of membrane glucose transport; its action on responsive cells alters the distribution of placental glucose transporters and may activate inactive ones. Dually perfused human placental lobule experiments found that maternal glucose levels exhibit a marked effect upon both glucose placental transfer and consumption. Specifically, when maternal glucose levels are above normal there is a corresponding increase in fetal blood glucose concentrations due to the increased supply transferred from the mother. Since maternal blood glucose concentration influences fetal glucose levels, both placental transport and consumption of glucose increase in response to maternal hyperglycemia . This is the hallmark of gestational diabetes. The response to hyperglycemia is often 2 fold. Firstly, glucose is stored as glycogen by the placenta. Although glycogen is present in the placenta throughout gestation, the trophoblast does not contain the rate limiting enzyme, glucose-6-phosphatase, needed to convert glycogen to glucose . As well, the increased glucose supply leads to an increase in its consumption . Elevated levels of insulin in the fetus become necessary to maintain homeostatic blood glucose concentration in lieu of increased glucose supply. Thus, maternal hyperglycemia will eventually lead to fetal hyperinsulimia, over nutrition and ultimately macrosomia in many unborn children. Despite being pharmacokinetically unaltered during pregnancy [25,26], insulin still presents a risk of transplacental transfer, and more importantly, non-compliance. Sulfonylureas, oral alternatives to insulin, are a class of drugs that appear to act by inhibiting potassium efflux via ATP dependent potassium channels in pancreatic b cells. This action leads to cellular depolarization and calcium-stimulated release of insulin in the pancreas. In other words, they enhance the release of endogenous insulin. Glibenclamide is a second generation sulfonylurea that has been shown not to cross the human placenta. A randomized control trial of 404 pregnant women suffering from gestational diabetes conducted by Langer et al. [26,27] found no detectable levels of glibenclamide in cord serum. Glibenclamide’s exceptionally high protein binding, above 99.8%, allows for less than 0.2% of free drug to circulate and cross the placenta. Additionally, its high protein binding is coupled to a short elimination half-life made possible by its low volume of distribution (0.2 l/kg) and rapid clearance (1.3 ml/kg/min). Simply put, glibenclamide has only a brief opportunity to cross the placenta [15,25]. Moreover, unlike insulin, glibenclamide does not elicit an immune response in either the baby or the mother. The unique interplay of pharmacokinetic parameters, such as high protein binding and short elimination half-life, is suspected to prevent it from crossing the placenta, and make it suitable for treatment in pregnancy. TREATMENT OF GESTATIONAL DIABETES PLACENTAL ABC TRANSPORTERS AND PREGNANCY The ultimate goal of gestational diabetes treatment is to restore normoglycemia in the mother thereby ensuring a euglycemic environment for the fetus. The gold standards for the management of gestational diabetes have been diet and insulin. For the gestational diabetic (mother), insulin promotes glucose uptake and oxidative metabolism resulting in a lowering of blood sugar, controlling glycosuria and polysuria as well as the disappearance of ketone bodies from the blood and urine . Insulin is the preferred pharmacological treatment in pregnancy because it is unable to cross the placenta due to its large molecular weight (6000 Da). However, insulin is not without its shortcomings. Elliott et al. [12,13] observed anti-insulin antibodies in response to human insulin in women with gestational diabetes. Once bound to these IgG antibodies, insulin can cross the placental barrier and initiate the cascade of events leading to neonatal macrosomia. Moreover, most women who suffer from gestational diabetes were not diabetic prior to pregnancy. Adequate normoglycemia in these women may require several daily injections; pain, discomfort as well as the increased cost and training required to administer these injections make compliance with the therapy a critical issue. The trophoblast is the interface of exchange between the maternal and fetal circulations. As a barrier, the trophoblast has abundant expression of ABC transporters such as P-glycoprotein (P-gP) and multidrug resistance proteins 1, 2 and 3 (MRP1, MRP2, MRP3, respectively). Powered by ATP, these transporters actively extrude substrates from the placenta  (Table 3). Particularly, P-gP and MRP2 have been shown to be expressed on the brush border (maternal-side) of the human placental trophoblast , while MRP1 and MRP3 are on the basal membrane (fetal side) [19,34]. Multidrug resistance transporters may result in a lower cellular concentration of drug via an efflux mechanism, thus creating pharmacological sanctuaries. For example, MRP1 and MRP3 preferentially transport organic anions, promote the excretion of glutathione/glucoronide metabolites and thus prevent their entry into fetal blood. P-gP is also an active drug transporter of the ATP binding cassette transporter family with a wide range of substrates . Abundant in the apical membrane of the placental trophoblast, P-gP transports its substrates in an outward (extracellular) direction. Since it can be detected in placental trophoblast from the first trimester of pregnancy [14,42] it is likely that it ARTICLE IN PRESS Gedeon, Koren: Designing Pregnancy Centred Medications 5 Table 3. Drug efflux transporters and substrates Substrates Actinomycine D Doxorubincin Irinotecan Mitroxantrone Teniposide Vinblastine Morphine Dexamethasone Beta-acetyldigoxin Transporter Etoposide Daunorubcin Mitomycin C Paclitaxel Topotecan Vincristine Loperamide Ketoconazole Alpha methyldigoxin Quinidine Indinavir Saquinavir Cyclosporine A Erythromycin Sparfloxacin Lovastatin Simvastatin Mibefradil D617, D620 Bisanterine Citalopram Corticosterone Loperamide Paclitaxel Prednisolone Rifampin (99 m)-Tctetrofosfine P-glycoprotein (MDR1) Adiamycin Glutathione Methotrexate Aflatoxin B1 Paclitaxel Vincristine Dehydroepiandrosterone Etoposide 17-beta glucoronyl estradiol S-glutathionyl Prostaglandin A2 Methotrexate Etoposide Mithoxantrone Organic anions Cisplatinum Topotecan Colchicine MRP1 multidrug resistance protein Methotrezate Vinblastine Ceftriaxone Rifampicin Ritonavir Estradiol Temocaprilate Pravastatin Heavy metals Food carcinogens Doxorubicin Epirubicin Phenytoin Cisplatin Vincristine Grepafloxacin Saquinavir Indinavir Octreotide Furosemide Flavonoids Arsenite Acetaminophen Etoposide Methotrexate Glucuronide Leukotriene C4 Teniposide Digitosin Amprenavir Nelfinavir Ritonavir Tacrolimus Levofloxacin Atorvastatin Cerivastatin Diltiazem Verapamil Aldosterone Calcein-M Colchicin FK 560 Ondasetron Phenytoin Quinidine Terfenadine Table 3 (continued) Substrates Topotecan Doxorubicin Danurubicin Zidovudine Lamivudine Mitoxantrone Methotrezate MTX-glu Adriamycin Transporter 9 Aminocamptotecin Irinotecan Epirubicin Idrubicinol Flavopiridol Prazocin Indolocarbazol Pheophorbide Etoposide BCRP breast cancer resistance protein protects the fetus from amphipathic xenotoxins. Thus, fetal tolerance to maternal concentrations of drugs which are considered to be good P-gP substrates will be higher than that for drugs considered to be poor P-gP substrates. Thus, it may be preferable to treat pregnant women with drugs that are good P-gP substrates such as during antineoplastic chemotherapy where drugs, such as PaclitaxelÒ may be preferred over other antineoplastic agents that cross the placenta more easily. ANTIRETROVIRALS IN PREGNANCY PSC833 Fluorscein MRP2 multidrug resistance protein Sulphinpyrazone Etoposide MRP3 multidrug resistance protein In contrast, there are clinical situations where it is desirable to increase the penetration of drugs in order to treat the unborn child. An important example is antiretroviral treatment of HIV-infected pregnant women. Data suggest that nucleoside reverse transcriptase inhibitors rapidly cross the placenta (Table 4). Cord blood concentrations of ZidovudineÒ and LamivudineÒ tend to equal maternal concentrations at the time of delivery, whereas cord blood concentrations of didanosine and zalcitabine are approximately 50% that of maternal concentrations [38,39]. Non-nucleotide reverse transcriptase inhibitors, such as nevirapine, have also been shown to cross the placenta [31,38]. Several factors may account for their passage including the drug’s lower protein binding (60%), low molecular weights, favorable degree of lipophilicity (log octanol/water coefficient 1.81) . As well, the majority are not P-gP substrates. Hence, these drugs passively diffuse across the placenta and are administered in sufficient doses to cross the placenta and prevent maternalefetal transmission of HIV during labor. Conversely, protease inhibitors (PI) do not cross the placenta to a clinically appreciable extent . Nelfinavir, ritonavir, saquinavir and lopinavir undergo incomplete transplacental transfer . Low PI placental transfer can be attributed to high protein binding (98%) and that these drugs are substrates for placental P-gP transporter . For example, Saquinavir is a P-gP substrate with a high molecular weight (767 g/mol), high protein binding (98%) and partition coefficient (octanol/water 4.1 log10) which may contribute to the small amount that crosses the placenta . Other protease inhibitors which follow similar placental kinetics include indinavir, ritonavir, lopinavir and nelfinavir. P-gP’s relative affinity to ARTICLE IN PRESS Placenta (2005), Vol. jj 6 Table 4. Pharmacokinetic changes in HIV drugs during pregnancy Drug class Drug Nucleoside reverse Zidovudine transcriptase inhibitors Lamivudine Didanosine Stavudine Half-life No change (1.1 h) No change (6 h) No change (1.5 h) No change Protein binding (%) Bioavailability Clearance <25 Increases No change 10e50 Increases Non-nucleoside Nevirapine reverse transcriptase inhibitors Unchanged Protease inhibitors Unchanged (3e5 h) 98 Lopinavir Unchanged (5e6 h) Amprenavir Unchanged (6 h) Saquinavir Hydroxicarbamide: not recommended in pregnancy 99 98 98 Nelfinavir Ritonavir Prone to induction 60 Placental transfer 63% Cross by diffusion 55% Cross by diffusion 45% Cross by diffusion 86% Cross by diffusion 90% Cross by diffusion Neural tube defect: not used in pregnancy Not detectable in cord blood 5.3% maternal [ ] detected in cord blood 6e8% of maternal [ ] in cord blood Not detectable in cord blood Source: [29,31,33,39e42]. different PI drugs varies 3e4 fold . Nelfinavir has become a commonly used protease inhibitor during pregnancy because of its tolerability and potency; however, it has also been demonstrated to exhibit a more rapid development of viral resistance and less durable suppression of viral replication leading to a greater likelihood of HIV transmission to the fetus. Saquinavir monotherapy is not adequate and often requires ‘‘boosting’’ with low dose ritonavir. Ritonavir is rarely used in pregnancy owing to its frequent and severe gastrointestinal adverse effects . Only 5.3% of maternal plasma concentrations of ritonavir are detected in fetal cord blood. Ritonavir’s well documented interaction and perhaps inhibition of P-gP and MRP1 may account for its exclusion from the placenta . However, ritonavir’s inhibition of these transporters is disadvantageous since it gives rise to drug exclusions, altered bioavailability and changes in drug distribution resulting in a decreased efficacy of treatment with time. This requires the initiation of combination therapies to achieve clinically beneficial and sustained viral suppression. Consequently, poly-therapy is usually accompanied by decreased adherence. However, if certain PI are effluxed by the placenta, and not reaching the fetus, future use of the appropriate ABC inhibitor may allow for greater concentrations in the fetal compartment and the prevention of maternalefetal HIV transmission. As the use of combination antiretroviral regimens becomes increasingly common among HIV-infected pregnant women and the rate of transmission decreases, the safety, toxicity and teratogenicity of these agents become paramount. For example, a common toxicity with zidovudine is bone marrow suppression, and decreases in hemoglobin in infants exposed to zidovudine at 3 weeks of age . As a class, nucleoside reverse transcriptase inhibitors have been suggested to cause fetal hepatic microsomal damage in infants exposed perinatally . Additionally, combination therapy has been suggested to trigger glucose intolerance. In particular, zidovudine in combination with lamivudine and nelfinavir fosters a reduction in neonatal insulin similar to that observed in Type I diabetes . These data may indicate an early damaging effect on fetal pancreas such as inhibition of proinsulin conversion to insulin due to the activity of these protease inhibitors. Cumulative damaging effects on pancreatic b cells may culminate in the death of these cells and consequent insulinopenia followed by clinical diabetes. GLIBENCLAMIDE’S INTERACTION WITH THE ABC-TRANSPORTER FAMILY Recently, we have shown, using the placental perfusion model, that glibenclamide is actively transferred from the fetal to the maternal circulations against a concentration gradient. Overall, there was a net decrease (63%) of glibenclamide in fetal to maternal concentration ratios despite equal initial concentrations (200 ng/ml) in both maternal and fetal circulation . Undoubtedly, placental active transporters such as the ABCtransporter family should be considered in the movement of glibenclamide from fetal to maternal circulation. From an in vitro perspective, glibenclamide is well known to interact with P-gP. However, the emerging thought is that glibenclamide may represent a general inhibitor for ABC transporters, both P-gP and MRP’s alike and other placental ARTICLE IN PRESS Gedeon, Koren: Designing Pregnancy Centred Medications homologue, in that it may bind to some conserved motif . Yet, the belief that glibenclamide is simply an inhibitor of these transporters is contradictory to in vivo findings. Elliott et al.’s  dually perfused human placental model showed virtually no appearance of glibenclamide in the fetal circulation. Even when maternal concentrations were 8 fold greater than therapeutic peak levels (1000 ng/ml), a relatively large concentration gradient facilitating the possibility for diffusion, only minimal concentrations of glibenclamide were seen in fetal blood. Diffusion, simple or facilitated, cannot explain the negligible presence of glibenclamide in the fetal compartment. As a substrate of certain members of the ABC-transporter family, glibenclamide may be actively pumped back to maternal circulation, and can both maintain maternal steady state concentrations and normoglycemia while decreasing fetal exposure and risk of hypoglycemia. Perhaps the possibility should be considered that glibenclamide is not an inhibitor of the ABC transporters but rather a substrate. GLIBENCLAMIDE: THE PROTOTYPE OF AN OPTIMAL DRUG FOR PREGNANCY The choice of therapy in pregnancy is a culmination of many factors: efficacy of the drug in treating the maternal condition, possibility of transplacental passage, risk of teratogenicity and abnormality due to this transplacental passage as well as factors influencing tolerability and adherence. In pregnancy, tolerability may be even more important especially if therapy exacerbates common complications of pregnancy such as morning sickness or glucose intolerance. Glibenclamide appears to fulfill all these characteristics. While it is well tolerated and fails REFERENCES  Agarwal M, Punnose J. Recent advances in the treatment of gestational diabetes. Expert Opin Investig Drugs 2004 Sept;13(9):1103e11.  Bawdon RE. The ex vivo human placental transfer of the anti-HIV antinucleoside inhibitor abacabir and the protease inhibitor amprenavir. Infect Dis Obstet Gynecol 1998;6(6):244e6.  Beck F. 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