Placenta drug metabolism

Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metabolism and Disposition The Biological Fate of Chemicals, 33, 94—101. 

Both in vitro and in vivo metabolic studies have shown that some drug metabolism occurs or can be induced in placental tissues (20). Further degradation of parent chloroquine that reaches the placenta would result in the appearance of less chloroquine and more of the nonpolar metabolites in the fetal or neonatal circulation. (17). 

Drug metabolism can occur in all tissues and most biological fluids. However, the widest range of metabolic reactions occurs in the liver. A more substrate-selective range of metabolic processes takes place in the kidney, lungs, brain, placenta and other tissues. 

PasanenM. 1999. The expression and regulation of drug metabolism in human placenta. Adv. DrugDeliv. Rev. 38 81-97... 

Pelkonen, O., louppila, P, and Karki, N. (1973). Attempts to induce drug metabolism in hnman fetal liver and placenta by the administration of phenobarbital to mothers. Arch. Int. Pharmacodyn. Ther. 202, 288-297. 

Low levels of drug metabolizing activity have been described in normal human placenta this system may have different subcellular localization and cofactor requirements than the hepatic system. However, the levels of benzpyrene hydroxylase in placenta are several fold higher in cigarette smokers than in non-smokers suggesting that some component of cigarette smoke, perhaps benzpyrene itself, may activate the placental system. 

The human placenta expresses a number of nutrient and efflux transporters, as well as metabolic enzymes. Information about the placental function and regulation of these systems, and how they interact with the administered drug, can help to target them appropriately so as to limit fetal exposure to harmful substances. 

The degree of exposure of the fetus to a particular substance can be best assessed in human subjects, but concerns of fetal safety have restricted the use of this approach. Moreover, clinical studies cannot elucidate the various mechanisms that contribute to transplacental transport of a particular compound. There are many structural differences between the human placenta and the placenta of other mammalian species, which complicates extrapolation of data obtained from in vivo animal models to humans [7], Thus, several ex vivo and in vitro techniques have been developed to study the placental role in drug transfer and metabolism during pregnancy and there are some excellent articles that discuss these systems in detail [7], Both isolated tissues and various cell culture techniques are currently in use and these have been summarized below. 

In addition to the above studies, a number of studies examining the pharmacokinetics of the test material need to be conducted to show whether the drug crosses the placenta, whether it is excreted in milk and whether pregnancy affects absorption, distribution, metabolism or excretion. 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

Brain development occurs in a complex series of events regulated by cellular and environmental interactions (Levitt, 1998). Most abused substances readily cross the placenta. Many are concentrated in the amniotic fluid and metabolized less efficiently by the fetus, exacerbating the teratogenic consequences of exposure. The effects of prenatal exposure to drugs of abuse... 

Two mechanisms help protect the fetus from drugs in the maternal circulation (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, /V-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. 

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