After oral administration of clopidogrel, about 50% of the dose is going to be absorbed by the intestine, once clopidogrel is delivered to the liver, is metabolized by two main metabolic pathways: an esterase-dependent pathway where it is hydrolysed by carboxylesterase 1 (CES1) to the inactive carboxylic acid metabolite (85–92% of circulating metabolites) and a cytochrome P450-dependent pathway leading to the drug bioactivation\cite{Jiang_2015,Djebli_2015}, because clopidogrel  in vivo requires biotransformation to be an active thiol metabolite \cite{lexicomp2020}.
First, 2-oxo-clopidogrel, an intermediate and pharmacologically inactive metabolite, is formed by cytochrome P450, which is then further converted into the pharmacologically active metabolite (clopi-H4) by the same pathway. In vitro enzyme kinetics studies have revealed that CYP1A2 (35.8%), CYP2B6 (19.4%) and CYP2C19 (44.9%) contribute to the formation of 2-oxo-clopidogrel, whereas CYP2B6 (32.9%), CYP2C9 (6.79%), CYP2C19 (20.6%) and CYP3A4 (39.8%) contribute to the formation of the active metabolite \cite{Jiang_2015}.
The onset of action is going to be dose-dependent, detected within 2 hours with a 300 to 600 mg loading dose and detected by the second day of treatment with a loading dose of 50 to 100 mg/day. The duration of action of the anti-platelet aggregation and bleeding time gradually return to baseline after ~5 days after discontinuation and the half-life elimination is ~ 6-8 hours \cite{lexicomp2020}.
Epidemiology
The CYP2C19*2 polymorphism, is also known as poor metabolizer because it has been related with a decreased enzymatic activity function \cite{Bergmeijer_2012}, specially in those who have the presence of the SNP in both alleles, that strongly suggest a reduction in clopidogrel matabolism leading to a decrease in its antiplatelet effect. According to a study performed with 51 mexican patients, 9 (17%) of them were found to carry the CYP2C19*2 polymorphism  \cite{Viveros_2016}. Of these, seven (13.7%) were heterozygotes and two (3.9%) were homozygous. The remaining 42 patients had the wild-type genotype. This results showed that 3.9% of patients had the homozygous genotype, wich is higher thant the previously reported frequency of 0-1.45% in the Mexican Mestizo groups \cite{Viveros_2016}.

Impact of polymorphism on clopidogrel metabolism

The focus on the responsiveness to clopidogrel based on the polymorphism expresed on the patient had lead to studies in healthy subjects on clopidogrel treatment and in ACS patients on dual antiplatelet treatment that showed the CYP2C19*2 allelic variant is an independent predictor of clopidogrel treatment variability  \cite{Giusti2007}
Initial studies have determined that carriers of the allelic variant (CYP2C19*2) have significantly lower levels of the active clopidogrel metabolite, which contributes to higher rate of cardiovascular events, including stent thrombosis\cite{Taubert2009}
Previous research indicate that CYP2C19, CYP1A2, and CYP2B6 participate in the first metabolic step, whereas CYP2C19, CYP2C9, CYP2B6, and CYP3A are responsible for the second step  \cite{Kazui2010} this is where CYP2C19*2 polymorphism becomes relevant because  previous research strongly suggests that variable and insufficient active metabolite generation is the main explanation for clopidogrel response variability and high on-treatment platelet reactivity (HTPR)  \cite{Angiolillo2004}
Clopidogrel is highly susceptible to drug interactions and CYP gene single nucleotide polymorphisms, thus reducing the in vitro enzyme activity inhibiting/reducing the conversion of clopidogrel into its active thiol metabolites \cite{Alvitigala2020} in this game the key role is played by the CYP2C19*2 loss-­of-function polymorphism that is a G681A nucleotide substitution at the junction of intron 4 and exon 5, which introduces a splicing defect resulting in a truncated, nonfunctional protein, responsible for the poor-metabolizer phenotype.  \cite{de1994}
Other different studies have evaluated this impact of CYP2C19*2 polymorphism on clopidogrel pharmacokinetics and pharmacodynamics in healthy volunteers. In a study  \cite{Fontana2007}  was demonstrated that the CYP2C19 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in 28 young, healthy male volunteers treated for 7 days with clopidogrel at 75 mg/d. Another study show in subjects treated with clopidogrel, the presence of the CYP2C19*2 polymorphism was significantly associated with lower exposure to clopidogrel active metabolite, lower inhibition of platelet aggregation at 4 hours, and poor responder status  \cite{Brandt2007} 
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups (Table \ref{455489}.).\cite{httpsdailymednlmnihgovdailymeddruginfocfmsetida9a3c560-2408-4dd0-9f83-ee3e3a549c7b}
Finally  in a study of 162 healthy subjects on 300 mg dose of clopidogrel, was confirmed that carriers of at least one CYP2C19 reduced-function allele (30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers. Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9% less than that observed in noncarriers.    \cite{Mega2009}