Search

Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization includeCYP2C19genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response. This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome.

The gastrointestinal (GI) transit behavior of and absorption from an amphotericin B (AmB) solid lipid nanoformulation (SLN) in rats was investigated. We aimed to estimate the gastric emptying time (GET) and cecal arrival time (CAT) of AmB SLN in rats as animal models. From these two parameters, an insight on the absorption window of AmB was ascertained. Three types of SLNs, AmB, paracetamol (PAR), and sulfasalazine (SSZ), were similarly formulated using beeswax/theobroma oil composite as the lipid matrix and characterized with regard to size, viscosity, density, migration propensity within agarose gel, in vitro drug release, morphology, gastrointestinal transit, and in vivo absorption. The GET and CAT were estimated indirectly using marker drugs: PAR and sulfapyridine (SP). All three types of SLNs exhibited identical properties with regard to z-average, viscosity, relative density, and propensity to migrate. PAR was absorbed rapidly from the small intestine following emptying of the SLNs giving the T50E (time for 50% absorption of PAR) to be 1.6 h. SP was absorbed after release and microbial degradation of SSZ from SLN in the colon with a lag time of 2 h post-administration, serving as the estimated cecal arrival time of the SLNs. AmB within SLN was favorably absorbed from the small intestine, albeit slowly.

Clopidogrel is crucial for dual antiplatelet therapy. However, clopidogrel attenuated response may cause therapeutic failure. Although CYP2C19 *2 and *3 alleles are associated with clopidogrel attenuated response, CYP2C19 genotyping is not sufficient to predict the response. Nuclear magnetic

Background. TheCYP2C19*2allele may be associated with a reduced antiplatelet effect for clopidogrel. Here, we assessed whetherCYP2C19*2alleles correlate with clopidogrel responsiveness following the administration of clopidogrel in healthy Malaysian volunteers.Methods. Ninety volunteers were genotyped forCYP2C19*2andCYP2C19*3alleles. Forty-five of 90 volunteers were included in the clopidogrel response studies and triaged into three genotypes, namely,CYP2C19*1/*1(n=17),CYP2C19*1/*2(n=21),andCYP2C19*2/*2(n=7). All subjects received 300 mg of clopidogrel, and platelet reactivity was assessed after a four-hour loading utilizing the VerifyNow-P2Y12 assay. Platelet activity was reported using P2Y12 reaction units (PRUs), and nonresponder status was prespecified at PRU ≥ 230.Results. Following clopidogrel intake,CYP2C19*2/*2carriers had a significantly higher mean PRU compared to theCYP2C19*1/*2andCYP2C19*1/*1(291.0 ± 62.1 versus 232.5 ± 81.4 versus 147.4 ± 87.2 PRU,P<0.001) carriers. Almost half of the participants (46.7%) were found to be nonresponders (3 wereCYP2C19*1/*1, 11 wereCYP2C19*1/*2, and 7 wereCYP2C19*2/*2).Conclusion. In healthy Malaysian volunteers,CYP2C19*2allele was associated with a decrease in platelet responsiveness to clopidogrel. However, clopidogrel nonresponders can be found not only in the carriers ofCYP2C19*2/*2, but also in the carriers ofCYP2C19*1/*2andCYP2C19*1/*1. The present paper demonstrated that genotype information does not correlate with clopidogrel response, and genotyping may represent a less robust approach compared to platelet activity testing in guiding clopidogrel therapy.