Transcript
0:00Two routes to the child
Lesson 3.4 of our distribution module: the placenta and breast milk. Distribution is the movement of a drug from the blood into the tissues and back. From the maternal blood, a drug can reach the child by two routes: the placenta before birth and breast milk after birth.
0:25The placenta
The first route is the placenta. A continuous layer of fused cells, the syncytiotrophoblast, is the main barrier between the maternal blood and the fetus, the unborn child. Passive diffusion is movement from a higher to a lower concentration, without energy use. Nearly all drugs reach the fetal blood to some extent by passive diffusion. Plasma is the liquid part of the blood. Drug bound to plasma proteins cannot cross the placenta, so binding slows the transfer. The efflux transporters P-glycoprotein and breast cancer resistance protein carry drugs back into the maternal blood. Fetal Kp,uu is the unbound drug concentration in fetal plasma divided by that in maternal plasma. At the end of pregnancy, it was below 0.25 for darunavir and lopinavir, two drugs that P-glycoprotein carries.
1:38Ion trapping in the fetus
Fetal plasma is slightly more acidic than maternal plasma. At a lower pH, a larger share of a weak base takes up a proton, a hydrogen ion, and becomes charged. The charged form crosses membranes slowly, so more of it stays in the fetal blood. This ion trapping can raise the fetal concentration above the maternal concentration.
2:08Breast milk
The second route is breast milk. The milk-to-plasma ratio is the drug concentration in milk divided by that in maternal plasma. The infant dose is the milk concentration times the daily milk intake per kilogram of infant weight. The relative infant dose is this dose as a percentage of the daily maternal dose per kilogram of maternal weight. A relative infant dose below 5 to 10 percent is usually taken as a safety threshold. Below 10 percent, infant plasma concentrations stay below those that treat adults, unless infants remove the drug much more slowly per kilogram than adults. As in the placenta, plasma protein binding limits drug transfer into milk. Milk has a lower pH than plasma, and ion trapping can hold some bases there. Active transport, by proteins that use energy, carries some drugs into milk. Of 28 drugs with known active transport, 17 had a milk-to-plasma ratio above 1, compared with 17 of 59 drugs without it.
3:37Maternal clearance
Clearance is the volume of plasma from which the body removes all the drug per unit time. The relative infant dose depends on the milk-to-plasma ratio and the maternal clearance. At a given dose, a low maternal clearance gives high plasma and milk concentrations. Phenobarbital has a low clearance. Its milk-to-plasma ratio is below 1, but its relative infant dose is 50 to 70 percent. Morphine has a high clearance. Its ratio is about 2, but its relative infant dose is about 5 percent.
4:22Lamotrigine
Lamotrigine, a drug for epilepsy, shows transfer by both routes. In 9 women, the lamotrigine concentration in umbilical cord plasma, which comes from the fetal blood, was similar to the maternal plasma concentration at delivery. At 72 hours after birth, the median infant plasma concentration was still 75 percent of the cord concentration. In the same women, 2 to 3 weeks after birth, the median milk-to-plasma ratio was 0.61. A second study collected 210 milk samples from 30 women who took lamotrigine and breastfed. The mean milk-to-plasma ratio was 0.41 and highly variable. In the same study, the infant dose was 0.51 milligrams per kilogram per day, and the relative infant dose was 9.2 percent. The infant plasma concentration, 18.3 percent of the maternal concentration, was about twice the relative infant dose. This agrees with the slow elimination of lamotrigine in the infants.
5:50Summary
In summary, nearly all drugs cross the placenta to some extent by passive diffusion. Plasma protein binding and efflux transporters slow the transfer, and the lower fetal pH can trap weak bases. In milk, ion trapping holds some bases, and active transport carries some drugs into milk. The relative infant dose depends on the milk-to-plasma ratio and the maternal clearance. For lamotrigine, the cord and maternal concentrations were similar. The relative infant dose was 9.2 percent, below 10 percent, the upper end of the usual 5 to 10 percent safety threshold. This concludes lesson 3.4 on the placenta and breast milk.
Sources
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
