Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated.

Cytochrome P450s (CYP450) family is one of the most critical factors in the metabolism process. Hence, the present study aims to characterize the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, and P-glycoprotein (P-gp) pump in patients with type 2 diabetes (T2DM). This characterization was performed before and after good glycemic control versus non-diabetic subjects following the administration of a substrate probe drug cocktail. This single-center clinical study proposes the characterization of T2DM impacts on major CYP450 drug-metabolizing enzyme and P-glycoprotein (P-gp) activities. The main propose of the present study is evaluating any alternation in major CYP450 enzymes and P-gp activities in patients with T2DM, before (A1C>7%) and after (A1C≤7%) good glycemic control along with comparing the activities versus non-diabetic subjects. The phenotypes will be assessed following the oral administration of a drug cocktail containing caffeine (CYP1A2), bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A4/5), and fexofenadine (P-gp) as probe substrates. Furthermore, the influence of variables such as glycemia, genetic polymorphisms, and inflammation on the metabolism process will be evaluated. The first patient has entered the study in Dec 2018.

The inter-individual variability of CYP450s enzyme activity may be reduced by comparing the effects of bariatric surgery on CYP-mediated drug elimination in comparable patients before and after surgery. The current research will use a low-dose phenotyping cocktail to simultaneously evaluate the activities of six CYP isoforms and P-gp. The results showed that following weight reduction after surgery, the activity of all enzymes increased compared to the obese period, which was statistically significant in the case of CYP3A, CYP2B6, CYP2C9, and CYP1A2. Furthermore, the activity of P-gp after surgery decreased without reaching a statistical significance (p-value > 0.05). Obese individuals had decreased CYP3A and CYP2D6 activity compared with the control group, although only CYP3A was statistically important. In addition, there was a trend toward increased activity for CYP1A2, CYP2B6, CYP2C9, and CYP2C19 in obese patients compared to the control group, without reaching statistical insignificance (p-value ≥ 0.05). After six months (at least), all enzymes and the P-gp pump activity were significantly higher than the control group except for CYP2D6. Ultimately, a greater comprehension of phenoconversion can aid in altering the patient’s treatment. Further studies are required to confirm the changes in the metabolic ratios of probes after bariatric surgery to demonstrate the findings’ clinical application. As a result, the effects of inflammation-induced phenoconversion on medication metabolism may differ greatly across persons and drug CYP pathways. It is essential to apply these results to the clinic to recommend dose adjustments.

Objective(s): Alteration in drug metabolism is very likely in diabetes mellitus. This study assessed changes in CYP2C19 enzymatic activity in the liver using omeprazole as a probe in the animal model of type II diabetes (T2DM) before and after treatment with metformin and cinnamon. Materials and Methods: Twenty-eight male Wistar rats were randomly divided into seven groups. Fourteen days after induction of type 2 diabetic mellitus (T2DM), rats in the test group received metformin, cinnamon, and metformin plus cinnamon daily for 14 days. On day 28, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing omeprazole as a CYP2C19 probe. Perfusate samples were analyzed by HPLC-UV to evaluate the activity of CYP2C19. Results: Mean metabolic ratio of omeprazole was changed from 0.091 +/- 0.005 in the control group to 0.054 +/- 0.005 in the untreated-diabetic rats. This average was increased inordinately to 0.218 +/- 0.036 in the treated rats with metformin. Interestingly, the administration of cinnamon in combination with metformin in diabetic rats caused the enzyme activity to return to (0.085 +/- 0.002) approximately the observed levels in the control group (0.091 +/- 0.005). Conclusion: Results showed that despite the suppression of the CYP2C19 enzyme activity in T2DM rats, metformin treatment could increase the enzyme activity. Simultaneous application of cinnamon and metformin can modulate the function of CYP2C19 to the observed level in the control group and make it more predictable to treat diabetes mellitus and fate of drugs that are metabolized by this enzyme.