The Placental Barrier

The membrane separating fetal blood from maternal blood in the intervillous space, the placental barrier, resembles other membranes, in that lipid-soluble substances diffuse readily but water- 

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Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

Myxedema and goiter are the main conditions for which thyroid preparations are indicated. The treatment of cretinism is difficult because it is recognized only at or after birth. Even if this disease could be diagnosed m utero, thyroid hormones do not readily cross the placental barrier. In addition, the fetus, as does a premature infant, rapidly deactivates the thyroid hormones. The halogen-free analogue DlMlT [26384-44-7] (3), which is resistant to fetal deiodinases, may prove useful for fetal hypothyroidism (cretinism). 

Hewitt M et al. (2007) Structure-based modelling in reproductive toxicology (Q)SARs for the placental barrier. SAR QSAR Environ Res 18(l-2) 57-76 Mekenyan O et al. (2003) In silico modelling of hazard endpoints current problems and perspectives. SAR QSAR Environ Res 14(5-6) 361-371... 

Discuss characteristics that affect drug transfer across the placental barrier and into breast milk. 

No studies addressing developmental or reproductive effects following acute inhalation exposure to aniline were located. However, because effects on development and reproduction arise after systemic uptake, oral administration of aniline can be considered for evaluating potential developmental and reproductive toxicity. Aniline (administered as aniline hydrochloride) readily crosses the placental barrier in rodents (Price et al. 1985). 

Grossly elevated concentrations of dissolved copper produce teratogenicity in fish embryos. A significant number of malformed fish larvae came from eggs treated with 500 pg Cu/L (Birge and Black 1979). In studies with laboratory animals and elevated concentrations of copper salts, copper penetrates the placental barrier into the fetus intramuscular injection of 4 mg Cu/kg BW early in pregnancy adversely affects fetal central nervous system development (Aaseth and Norseth 1986). In humans, no definitive data are available on whether copper can cause birth defects however, incubation of human spermatozoa with metallic copper results in loss of sperm motility (Aaseth and Norseth 1986). 

In Vitro Models and Multidrug Resistance Mechanisms of the Placental Barrier... 

C. Ampasavate, G.A. Chandorkar, D.G. Vande Velde, J.F. Stobaugh, and K.L. Audus. Transport and metabolism of opioid peptides across BeWo cells, an in vitro model of the placental barrier. Int I Pharm. 233 85-98 (2002). 

Placental Barrier The placental barrier consists of several layers of cells between the maternal and fetal circulatory systems. Diffusion of polar drugs is limited. However, lipid-soluble drugs can pass through the barrier. Fetuses are rich in lipids and may form a reservoir for sequestering lipid-soluble drugs. 

However, it had not been discovered that the thalidomide drug molecule could cross the placental barrier and affect fetal development. As a result, thousands of babies were born with crippled extremities, disfigurement, and disabilities. Numerous fetuses were stillborn or died soon after birth. 

Neonatal Cocaine freely crosses the placental barrier, and prenatal exposure to cocaine alters neurobehavioral development in rat pups (Sobrian et al. 1990). The effects on humans exposed prenatally to cocaine is a complicated matter, because so many other concurrent factors contribute to development. Common confounds are prenatal care and maternal polydrug use. Prenatal cocaine use is associated with reduced gestational age, birth weight, body length, and head circumference (Richardson et al. 1999). In children exposed prenatally to cocaine, some studies have shown behavioral differences evident at 1 to 3 years of age (Richardson et al. 1993 Richardson 1998). Associations are also made with impulsivity and attention deficits at age 6 (Leech et al. 1999). 

Harmala alkaloids are potent inhibitors of monoamine oxidase (Callaway and Grob 1998). Thus, if combined with other antidepressants, such as selective serotonin reuptake inhibitors, there is potential for serious side effects. Harmaline or its metabolites also cross the placental barrier (Okonmah et al. 1988). 

A small number of fetal cells cross the placental barrier and circulate in the mother s bloodstream. These can be isolated from a sample of the mother s blood using cell-sorting techniques, and DNA can be amplified by PCR for genetic diagnosis. Although still experimental, this technique offers the advantage that there is no risk of fetal loss as a result of the procedure. 

Pentazocine has been successfully used to relieve labour pain [201] and its obstetric use in place of pethidine is favoured by,its apparent inferior ability to pass the placental barrier [206]. A clinical trial of (+)- and (-)-pentazocine adds to the rare number of examples in which optical enantiomorphs have been evaluated [207]. In post-operative patients, response to 60 mg of the dextro isomer was less than that to 5 mg of morphine, while 25—29 mg of (-)-pentazocine was as effective as 10 mg of morphine. Hence most of the activity of the race-mate resides in the laevo isomer, as anticipated from results in animals [208]. Several studies of the distribution, excretion and metabolism of pentazocine have been made. Peak levels of the tritium-labelled drug (and its c/s-3-chloroallyl analogue) were present in the C.N.S. of a cat within 40 minutes of intramuscular administration [209], the comparable figure for morphine being 2 hours [210]. 

Reproductive effects from lead exposure have been documented in animals and human beings of both sexes. High occupational exposure levels in pregnant women have been associated with increased incidences of spontaneous abortions, miscarriages, and stillbirths. Some studies also seem to indicate that prenatal exposure to lower levels of lead may increase the risk of preterm delivery and reduced birth weight. Lead penetrates the placental barrier and has caused congenital abnormalities in animals. There is no conclusive evidence, however, that low-level lead exposure leads to an increased incidence of... 

Absorption/Disthbutton - Following oral administration, methyidopa is variably absorbed. The mean bioavailability is approximately 50%. Methyidopa crosses the blood-brain barrier and is converted in the CNS to active alpha-methyinoradrenaline. Methyidopa crosses the placental barrier and appears in cord blood and breast milk. A decrease in BP occurs within 4 to 6 hours following IV or oral administration and lasts 10 to 16 hours or 12 to 24 hours, respectively. 

Labor - Narcotics cross the placental barrier and can produce depression of respiration and psycho-physiologic effects in the neonate. 

Pregnancy Category B. Mesalamine is known to cross the placental barrier. Lactation Low concentrations of mesalamine and higher concentrations of N-acetyl-5-ASA have been detected in breast milk. 

Pregnancy Chloramphenicol readily crosses the placental barrier cautious use is particularly important during pregnancy at term or during labor because of potential toxic effects on the fetus. 

Distribution - INH readily diffuses into all body fluids (including cerebrospinal, pleural, and ascitic), tissues, organs, and excreta (saliva, sputum, feces). It also passes through the placental barrier and into breast milk in concentrations comparable to those in plasma. 

Distribution - Tinidazole is distributed into virtually all tissues and body fluids and crosses the blood-brain barrier. The apparent volume of distribution is approximately 50 L. Plasma protein binding of tinidazole is 12%. Tinidazole crosses the placental barrier and is secreted in breast milk. 

Developmental Toxicity. No studies were located regarding the developmental effects of thorium in humans or animals following exposure by any route. Also, pharmacokinetic data do not exist that may predict whether thorium crosses the placental barrier. Further developmental studies in animals by all relevant routes of exposure may clarify the potential developmental effects of thorium in humans. 

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