Placental drug metabolism

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). 

Kolwankar, D., et al. (2005). Expression and function of ABCBl and ABCG2 in human placental tissue. Drug Metabolism and Disposition The Biological Fate of Chemicals, 33(4), 524—529. 

Hassoun EA, Walter AC, Alsharif NZ, Stohs SJ (1997) Modulation of TCDD-induced fetotoxicity and oxidative stress in embryonic and placental tissues of C57BL/6J mice by vitamin E succinate and ellagic acid. Toxicology 124 27-37 Hemandez-Ochoa I, Karman BN, Flaws JA (2009) The role of the aryl hydrocarbon receptor in the female reproductive system. Biochem Pharmacol 77 547-559 Hines RN (2008) The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther 118 250-267... 

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. 

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]. 

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. 

Tetrahydrocannabinol is metabolized in the liver to form active metabolites which are further metabolized to inactive polar compounds these are excreted in the urine. Some metabolites are excreted into the bile and then recycled via the enterohepatic circulation. Because of their high lipophilicity, most active metabolites are widely distributed in fat deposits and the brain, from which sources they are only slowly eliminated. The half-life of elimination for many of the active metabolites has been calculated to be approximately 30 hours. Accordingly, accumulation occurs with regular, chronic dosing. Traces of the cannabinoids can be detected in the blood and urine of users for many days after the last administration. There is some evidence of metabolic tolerance occurring after chronic use of the drug. THC and related cannabinoids readily penetrate the placental barrier and may possibly detrimentally affect foetal development. 

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