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S-Mephenytoin

Chemically, Mephenytoin is 3-methyl-5, 5-phenyl-ethyl-hydantoin that is also known as Mesantoin. Mephenytoin is a molecule, that can be clinically used as a pharmaceutically active drug therapeutic drug.  For any pharmaceutically active drug, its structural features are the single primary factor that not only determines the site of biochemical transformation during metabolism but also the rate of that biochemical transformation. The molecular structure of Mephenytoin is shown in Figure 1, while the existence of a chiral carbon at carbon number 5 and its chemical implications in terms of existence of Mephenytoin as a racemic mixture, are diagrammatically demonstrated in Figure 2.

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Figure 1 The Molecular Structure of Mephenytoin; looking it closely, it contains two rings. One is aromatic while other one is hydantoin.

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Figure 2 The Molecular Structure of Mephenytoin; All the carbons in the carbon backbone along with the heterogenous atoms, that is arranged in two distinct rings are numbered. Here Carbon number 5 is covalently bonded to one heterogenous atom, i.e., nitrogen. This makes Carbon number 5 a chiral carbon, that is also called as center of asymmetry. This existence of the chiral carbon in the overall molecular structure is the fundamental reason why Mephenytoin exists in two distinct isomers. S-Mephenytoin and R-Mephenytoin.

S-Mephenytoin is a human metabolite, i.e., that essentially means it get biochemically transformed by the activity of any molecule, particularly enzyme, only in the human body specifically in the liver. In other words, it is completely integrated into the body’s normal metabolism and becomes a part of it.  Inside the body, it is metabolized by CYP2C19 that is a protein, i.e., enzyme, that is one of the Cytochrome P450 (CYP) proteins. This relationship between CYP2C19 and S-Mephenytoin is diagrammatically illustrated in Figure 3.

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Figure 3 The relationship between CYP2C19 and S-Mephenytoin: the latter acts as a substrate which is metabolized by CYP2C19 protein in the human liver

Apart from metabolizing S-Mephenytoin, the CYP2C19 protein is also involved in the metabolism of a wide range of different important pharmaceutical drugs, i.e., especially those which are clinically therapeutic. Thus, from this it is quite clear that CYP2C19 protein is highly non-specific in its actions.

The gene that codes for CYP2C19 protein exhibits genetic polymorphism. This essentially means that the CYP2C19 protein is translated from little bit different nucleotide sequences in the gene among different human populations. Therefore, the primary structure of CYP2C19 protein gets changed across different individuals of the Homo sapiens; that eventually leads to different folding patterns, i.e., secondary as well as tertiary structure. Thereby, the metabolizing capacity of the CYP2C19 protein get altered. Due to genetic polymorphism, different degrees of metabolism of the pharmaceutically active components, including S-Mephenytoin, by CYP2C19 protein is demonstrated in the human individuals. In short, S-Mephenytoin metabolism is a variable in the human population. The human population can be broadly divided into two groups, based on the level of S-Mephenytoin metabolism namely: first is Poor Metabolizers (PMs), while other one is Extensive Metabolizers (EMs). Poor Metabolizers (PMs) are those individuals who metabolize S-Mephenytoin at a low rate as they have inactive CYP2C19 protein, while Extensive Metabolizers (EMs) are those individuals who metabolize S-Mephenytoin at a high rate as they have active CYP2C19 protein. The incidence and prevalence of either being Poor Metabolizers (PMs) or Extensive Metabolizers (EMs) is found in different research studies across a broad spectrum of different human populations. It is a scientifically established fact that reduced S-Mephenytoin metabolism which is a phenotypic trait, that is inherited as a recessive trait in nature with the mutations particularly in the autosomal chromosomes.

Due to the association of the genetic polymorphism with the CYP2C19 protein, it is always recommended to perform genotyping via using any of the valid and standard techniques before treating with S-Mephenytoin or any pharmaceutically active drug which is a molecular substrate for the CYP2C19 protein. Genotyping is a method by which the genetic variations, which are also known as DNA mutations are identified. This way, Poor Metabolizers (PMs) can be identified; they should not be treated with the CYP2C19 substrates. By adopting this strategy, potential side effects associated with the CYP2C19 substrates can be clinically avoided.

Mephenytoin is an active pharmaceutical drug with a therapeutic effect of being anticonvulsant. Therefore, it can be clinically used in the treatment of epilepsy in future. Chemically, it is a racemate of two stereo isomers; S-Mephenytoin and R-Mephenytoin. Both of these isomers are metabolized by the CYP2C19 protein but in a different manner, i.e., through different biochemical reactions. Therefore, this metabolism is termed as stereoselective metabolism, owning to the stereoselective nature of the CYP2C19 protein. The stereoselective metabolism arises when there exists a significantly high difference between the diastereomeric configuration of the complex between a chiral drug and enzyme. This complex can be generalized as an Enzyme Substrate Complex (ES Complex). In simple words, the Enzyme Substrate Complex (ES Complex) formed by the CYP2C19 protein with S-Mephenytoin and R-Mephenytoin, independently and respectively has a mutual difference in terms of spatial configuration. This is why both S-Mephenytoin and R-Mephenytoin are metabolized by the same enzyme protein, i.e., CYP2C19, differently.

As explained earlier, S-Mephenytoin and R-Mephenytoin are metabolized by the same CYP2C19 protein but through different biochemical reactions that lead to the formation of two entirely different chemicals. S-Mephenytoin is biochemically hydroxylated at the carbon number 4 of the benzene/ aromatic ring, i.e., hydroxylation is the chemical reaction in which hydroxyl functional group is added to the substrate. By this chemical reaction, one hydroxyl functional group is attached with the carbon number 4 of the benzene/ aromatic ring. This results in the formation of 4-OH-Mephenytoin, which is then biochemically conjugated to the glucuronic acid that is later eliminated from the body in the form of urine. Conjugation is a specialized type of biochemical reaction in which two compounds belonging to different classes are joined and the products are called as conjugated molecules. On the other hand, R-Mephenytoin is biochemically demethylated at the nitrogen position 3 of the hydantoin/ non-aromatic ring, i.e., Demethylation is the chemical reaction in which methyl functional group is removed the substrate. By this chemical reaction, one methyl functional group is removed from the nitrogen position 3 of the hydantoin/ non-aromatic ring. This results in the formation of PEH or Nirvanol, it is also eliminated from the body with urine but without any further biochemical transformation like conjugation. Keep in mind that both of these different metabolic processes are mediated and catalyzed by the same enzyme, i.e., CYP2C19. Both of these biochemical transformations are diagrammatically depicted in Figure 4.

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Figure 4 Two Distinct Metabolic Reactions for the same chemical compound, i.e., Mephenytoin: One is Aromatic Hydroxylation that leads to the formation of 4-OH-M, and other is Oxidative Demethylation that leads to the formation of PEH or Nirvanol 

In a clinical trial of the research study on the therapeutic effects Mephenytoin of on the epileptic patients. In this study, toxic effect is shown in only eight percent of people. Positive outcomes have been shown in the rest of the subjects.



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