Biol Psychiatry Glob Open Sci. 2022 Apr;2(2):115-126. doi: 10.1016/j.bpsgos.2021.07.008.

ABSTRACT

BACKGROUND: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.

METHODS: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.

RESULTS: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.

CONCLUSIONS: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

PMID:35712048 | PMC:PMC9117153 | DOI:10.1016/j.bpsgos.2021.07.008

J Gastrointest Cancer. 2022 Jun 16. doi: 10.1007/s12029-022-00840-0. Online ahead of print.

ABSTRACT

PURPOSE: The variability on irinotecan (IRI) pharmacokinetics and toxicity has been attributed mostly to genetic variations in the UGT1A1 gene, responsible for conjugation of the active metabolite SN-38. Also, CYP3A mediates the formation of inactive oxidative metabolites of IRI. The association between the occurrence of severe adverse events, pharmacokinetics parameters, and UGT1A1 and CYP3A4 predicted phenotypes was evaluated, as the evaluation of [SN-38]/IRI dose ratio as predictor of severe adverse events.

METHODS: Forty-one patients undergoing IRI therapy were enrolled in the study. Blood samples were collected 15 min after the end of drug the infusion, for IRI, SN-38, SN-38G, bilirubin concentrations measurements, and UGT1A1 and CYP3A genotype estimation. Data on adverse event was reported.

RESULTS: Fifteen patients (36.5%) developed grade 3/4 adverse events. A total of 9.8% (n = 4) of the patients had UGT1A1 reduced activity phenotype, and 48.7% (n = 20) had UGT1A1 and 63.4% (n = 26) CYP3A intermediary phenotypes. Severe neutropenia and diarrhea were more prevalent in patients with reduced UGT1A1 in comparison with functional metabolism (50% and 75% versus 0% and 13%, respectively). SN-38 levels and its concentrations adjusted by IRI dose were significantly correlated to toxicity (rs = 0.31 (p = 0.05) and rs = 0.425 (p < 0.01)). The [SN-38]/IRI dose ratio had a ROC curve of 0.823 (95% CI 0.69-0.956) to detect any severe adverse event and 0.833 (95% CI 0.694-0.973) to detect severe diarrhea. The cut-off of 0.075 ng mL-1 mg-1 had 100% sensitivity and 65.7% specificity to predict severe diarrhea.

CONCLUSION: Our data confirmed the relevance of the pre-emptive genotypic information of UGT1A1. The [SN-38]/IRI ratio, measured 15 min after the end of the IRI infusion, was a strong predictor of severe toxicity and could be applied to minimize the burden of patients after IRI administration.

PMID:35710870 | DOI:10.1007/s12029-022-00840-0

Pharmacogenomics J. 2022 Jun 16. doi: 10.1038/s41397-022-00281-9. Online ahead of print.

ABSTRACT

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, pcorrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.

PMID:35710824 | DOI:10.1038/s41397-022-00281-9

Pharmacol Rev. 2022 Jul;74(3):552-599. doi: 10.1124/pharmrev.120.000121.

ABSTRACT

The nitrogen mustards are powerful cytotoxic and lymphoablative agents and have been used for more than 60 years. They are employed in the treatment of cancers, sarcomas, and hematologic malignancies. Cyclophosphamide, the most versatile of the nitrogen mustards, also has a place in stem cell transplantation and the therapy of autoimmune diseases. Adverse effects caused by the nitrogen mustards on the central nervous system, kidney, heart, bladder, and gonads remain important issues. Advances in analytical techniques have facilitated the investigation of the pharmacokinetics of the nitrogen mustards, especially the oxazaphosphorines, which are prodrugs requiring metabolic activation. Enzymes involved in the metabolism of cyclophosphamide and ifosfamide are very polymorphic, but a greater understanding of the pharmacogenomic influences on their activity has not yet translated into a personalized medicine approach. In addition to damaging DNA, the nitrogen mustards can act through other mechanisms, such as antiangiogenesis and immunomodulation. The immunomodulatory properties of cyclophosphamide are an area of current exploration. In particular, cyclophosphamide decreases the number and activity of regulatory T cells, and the interaction between cyclophosphamide and the intestinal microbiome is now recognized as an important factor. New derivatives of the nitrogen mustards continue to be assessed. Oxazaphosphorine analogs have been synthesized in attempts to both improve efficacy and reduce toxicity, with varying degrees of success. Combinations of the nitrogen mustards with monoclonal antibodies and small-molecule targeted agents are being evaluated. SIGNIFICANCE STATEMENT: The nitrogen mustards are important, well-established therapeutic agents that are used to treat a variety of diseases. Their role is continuing to evolve.

PMID:35710137 | DOI:10.1124/pharmrev.120.000121

Hum Mol Genet. 2022 Jun 16:ddac132. doi: 10.1093/hmg/ddac132. Online ahead of print.

ABSTRACT

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

PMID:35708486 | DOI:10.1093/hmg/ddac132

Expert Opin Drug Discov. 2022 Jun 16. doi: 10.1080/17460441.2022.2090540. Online ahead of print.

ABSTRACT

Precision medicine leverages molecular biomarkers for selecting optimal treatment strategies. Accordingly, stratifying patients into responder and non-responder has strongly accelerated drug discovery and drug approvals in the last two decades. Recently, the applications of artificial intelligence (AI) in healthcare have been promoting these processes, and continue to improve patient care through systematically analysing large-scale molecular data and electronic health records. In particular, preclinical pharmacogenomics data empowered AI to unfold its full potential.Areas covered: Here, we discuss the opportunities of AI in pharmacogenomics, drug discovery and precision medicine. In particular, we shed some light on the advancements in computational biomedicine from statistical, machine learning (ML) to complex deep learning (DL) models.Expert opinion: AI has already strongly impacted drug discovery, and will continue to revolutionise academic research and the pharmaceutical industry. Its algorithms aid the identification of novel treatment options through molecular signatures and thus pave the way for the next generation of precision medicine.

PMID:35708267 | DOI:10.1080/17460441.2022.2090540

Glob Med Genet. 2022 Jun 13;9(2):63-71. doi: 10.1055/s-0041-1741109. eCollection 2022 Jun.

ABSTRACT

Diabetes has become a pandemic as the number of diabetic people continues to rise globally. Being a heterogeneous disease, it has different manifestations and associated complications in different individuals like diabetic nephropathy, neuropathy, retinopathy, and others. With the advent of science and technology, this era desperately requires increasing the pace of embracing precision medicine and tailoring of drug treatment based on the genetic composition of individuals. It has been previously established that response to antidiabetic drugs, like biguanides, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and others, depending on variations in their transporter genes, metabolizing genes, genes involved in their action, etc . Responsiveness of these drugs also relies on epigenetic factors, including histone modifications, miRNAs, and DNA methylation, as well as environmental factors and the lifestyle of an individual. For precision medicine to make its way into clinical procedures and come into execution, all these factors must be reckoned with. This review provides an insight into several factors oscillating around the idea of precision medicine in type-2 diabetes mellitus.

PMID:35707783 | PMC:PMC9192178 | DOI:10.1055/s-0041-1741109

Glob Med Genet. 2022 Feb 25;9(2):90-96. doi: 10.1055/s-0042-1743567. eCollection 2022 Jun.

ABSTRACT

Tuberculosis (TB) continues to be a major infectious disease affecting individuals worldwide. Current TB treatment strategy recommends the standard short-course chemotherapy regimen containing first-line drug, i.e., isoniazid, rifampicin, pyrazinamide, and ethambutol to treat patients suffering from drug-susceptible TB. Although Mycobacterium tuberculosis , the causing agent, is susceptible to drugs, some patients do not respond to the treatment or treatment may result in serious adverse reactions. Many studies revealed that anti-TB drug-related toxicity is associated with genetic variations, and these variations may also influence attaining maximum drug concentration. Thus, inter-individual diversities play a characteristic role by influencing the genes involved in drug metabolism pathways. The development of pharmacogenomics could bring a revolution in the field of treatment, and the understanding of germline variants may give rise to optimized targeted treatments and refine the response to standard therapy. In this review, we briefly introduced the field of pharmacogenomics with the evolution in genetics and discussed the pharmacogenetic impact of genetic variations on genes involved in the activities, such as anti-TB drug transportation, metabolism, and gene regulation.

PMID:35707778 | PMC:PMC9192167 | DOI:10.1055/s-0042-1743567

Drug Metab Pers Ther. 2022 Jun 15. doi: 10.1515/dmpt-2021-0222. Online ahead of print.

ABSTRACT

OBJECTIVES: Patients undergoing cardiac surgery develop post-sternotomy pain syndrome. The aim of this study was evaluation of the influence of CYP2C9, PTGS-1 and PTGS-2 genes polymorphisms on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

METHODS: The study included 90 patients undergoing cardiac surgery. A real-time polymerase chain reaction was used for the detection of single nucleotide polymorphisms (SNP). Pain intensity was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury (AKI) was determined by Kidney Disease Improving Global Outcomes criteria.

RESULTS: Pain intensity by the NRS score was significantly higher in patients with CYP2C9*3 АA genotype compared to АC genotype: 7 [1,10] and 6 [2,7] (p=0.003); 7 [1,10] and 6 [2,7] (p=0.04); 6 [0; 10] and 5 [2,6] (p=0.04); 5 [0; 8] and 3 [0; 8] (p=0.02), on days 1, 2, 3 and 5 in the postoperative period, respectively. GSRS score was higher in patients with CYP2C9*2 CT genotype compared to CС genotype: 19 [15; 42] and 18 [15,36] (p=0.04), respectively. There were no significant differences in the pain intensity, dyspepsia severity and AKI frequency in patients with homozygous and heterozygous genotypes for PTGS-1 rs10306135, PTGS-1 rs12353214, PTGS-2 rs20417.

CONCLUSIONS: CYP2C9*3 and CYP2C9*2 gene polymorphisms may affect efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

PMID:35705023 | DOI:10.1515/dmpt-2021-0222

Cancer Gene Ther. 2022 Jun 14. doi: 10.1038/s41417-022-00483-0. Online ahead of print.

ABSTRACT

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has dramatically impaired the clinical outcomes in non-small cell lung cancer (NSCLC) patients, but the mechanisms are still unclear in substantial cases. In our previous study, we demonstrated that a novel long non-coding RNA (lncRNA), lnc-ABCA12-8, was overexpressed in gefitinib-resistant NSCLC cells, but the exact function is unknown. In this study, we confirmed that lnc-ABCA12-8 was significantly upregulated both in NSCLC cell lines and the plasma samples of NSCLC patients with acquired resistance to gefitinib. Downregulation of lnc-ABCA12-8 could reverse gefitinib resistance both in vitro and in vivo. Mechanistically, lnc-ABCA12-8 interacted with alternative splicing factor/splicing factor 2 (ASF/SF2), promoted the binding of ASF/SF2 to the IIICS exon of fibronectin 1 (FN1) gene and enhanced the IIICS region inclusion during fibronectin 1 (FN1) alternative splicing, resulting in the upregulation of entire IIICS region, and enhanced cell proliferation, migration, invasion, and adhesion. Taken together, our study suggest that lnc-ABCA12-8 is involved in the acquired resistance to gefitinib, and may be a novel biomarker and therapeutic target for monitoring and overcoming gefitinib resistance in NSCLC.

PMID:35701616 | DOI:10.1038/s41417-022-00483-0

Drug Metab Dispos. 2022 Jun 14:DMD-AR-2022-000930. doi: 10.1124/dmd.122.000930. Online ahead of print.

ABSTRACT

Cytochromes P450 (P450 or CYP) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized. The cDNAs of these CYP2Js contained open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and shared high sequence identity (77-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven CYP2J genes contain nine coding exons and are located in corresponding genomic regions, with the pig CYP2J genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in small intestine with additional expression in kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocity-versus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. Significance Statement New dog cytochrome P450 2J2 (CYP2J2); cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in small intestine, similar to human CYP2J2.

PMID:35701183 | DOI:10.1124/dmd.122.000930

J Clin Pathol. 2022 Jun 14:jclinpath-2022-208308. doi: 10.1136/jclinpath-2022-208308. Online ahead of print.

ABSTRACT

In the era of personalised medicine, testing for an increasing number of predictive biomarkers is becoming a priority. However, tissue biopsies from these patients are oftentimes insufficient for conventional approaches, a common issue that deprives them of the clinical benefits of biomarker-directed treatments. To tackle this problem, many clinical laboratories are resorting to circulating tumour DNA (ctDNA), which is becoming increasingly appreciated as a valuable source for biomarker testing. In this context, next-generation sequencing (NGS) has become essential. Indeed, different NGS systems are able to detect several clinically relevant low-frequency hot-spot mutations simultaneously in a single run. However, their reproducibility in the analysis of ctDNA has not yet been investigated. The purpose of this study was to evaluate the reproducibility of using Illumina MiSeq and Thermo Fisher Ion S5 Plus platforms to assess pathogenic alterations in non-small cell lung cancer (NSCLC) liquid biopsy specimens. Using the in vitro diagnostic (IVD) NGS panel Myriapod NGS Cancer panel DNA (Diatech Pharmacogenetics) on MiSeq platform (Illumina), we reanalysed ctDNA extracted from a retrospective series of n=40 patients with advanced NSCLC previously tested with a custom NGS panel (SiRe) on Thermo Fisher Ion S5 Plus system. Overall, 13 out of 40 (32.5%) ctDNA samples displayed pathogenic alterations in at least two genes, namely, EGFR and KRAS A concordance rate of 100% was identified between the two methodologies in terms of sample mutational status and total number of detected variables. All NGS platforms featured a high degree of concordance.

PMID:35701144 | DOI:10.1136/jclinpath-2022-208308

J Pharm Sci. 2022 Jun 11:S0022-3549(22)00253-2. doi: 10.1016/j.xphs.2022.06.009. Online ahead of print.

ABSTRACT

Long-term use of cytotoxic agents promotes drug-resistance in triple-negative breast cancer (TNBC). The identification of new drug combinations with efficacy against drug-resistant TNBC cells in vitro is valuable in developing new clinical strategies to produce further cancer remissions. We undertook combination analysis of the cytotoxic agent ixabepilone with small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and poly (ADP-ribose) polymerase (PARP) in taxane-sensitive (231C) and taxane-resistant (TXT) MDA-MB-231-derived cells. As single agents, the VEGFR inhibitors cediranib and bosutinib decreased both 231C and TXT cell viability, but four other VEGFR inhibitors and two PARP inhibitors were less effective. Combinations of ixabepilone with either cediranib or bosutinib synergistically decreased 231C cell viability. However, only the ixabepilone/cediranib combination was synergistic in TXT cells, with predicted 15.3-fold and 1.65-fold clinical dose reductions for ixabepilone and cediranib, respectively. Flow cytometry and immunoblotting were used to further evaluate the loss of cell viability. Thus, TXT cell killing by ixabepilone/cediranib was enhanced over ixabepilone alone, and expression of proapoptotic cleaved caspase-3 and the Bak/Bcl-2 protein ratio were increased. These findings suggest that the synergistic activity of the ixabepilone/cediranib combination in taxane-sensitive and taxane-resistant cells may warrant clinical evaluation in TNBC patients.

PMID:35700798 | DOI:10.1016/j.xphs.2022.06.009

Pharmacogenomics. 2022 Jun 14. doi: 10.2217/pgs-2022-0052. Online ahead of print.

ABSTRACT

Aim: To investigate whether the TNIK gene affects risperidone treatment outcomes in the Chinese population. Methods: A total of 148 unrelated inpatients who received risperidone for six weeks were enrolled. The selected single nucleotide polymorphisms (SNPs; rs2088885, rs7627954 and rs13065441) were genotyped using the MassARRAY® SNP IPLEX platform. Results: The analysis showed that one novel SNP of TNIK, rs7627954, had a significant association with the response to risperidone (χ2 = 4.472; p = 0.034). This work also identified rs2088885 as significantly associated with risperidone response (χ2 = 5.257; p = 0.022). The result revealed that the rs2088885-rs7627954 C-T haplotype was more prevalent in good responders than in poor responders (p = 0.0278). Conclusion: This study revealed that the rs2088885 and rs7627954 SNPs of TNIK are associated with risperidone treatment response.

PMID:35698907 | DOI:10.2217/pgs-2022-0052

Pharmacogenomics. 2022 Jun 14. doi: 10.2217/pgs-2022-0062. Online ahead of print.

ABSTRACT

Tweetable abstract Pharmacogenomics cascade testing in a digital health solution can improve medication adherence in dementia care for disadvantaged populations.

PMID:35698906 | DOI:10.2217/pgs-2022-0062

Pharmacogenomics. 2022 Jun 14. doi: 10.2217/pgs-2022-0027. Online ahead of print.

ABSTRACT

Drug-induced long QT syndrome (diLQTS) is an adverse effect of many commonly prescribed drugs, and it can increase the risk for lethal ventricular arrhythmias. Genetic variants in pharmacodynamic genes have been associated with diLQTS, but the strength of the evidence for each of those variants has not yet been evaluated. Therefore, the purpose of this review was to evaluate the strength of the evidence for pharmacodynamic genetic variants associated with diLQTS using a novel, semiquantitative scoring system modified from the approach used for congenital LQTS. KCNE1-D85N and KCNE2-T8A had definitive and strong evidence for diLQTS, respectively. The high level of evidence for these variants supports current consideration as risk factors for patients that will be prescribed a QT-prolonging drug.

PMID:35698903 | DOI:10.2217/pgs-2022-0027

J Gene Med. 2022 Jun 13:e3436. doi: 10.1002/jgm.3436. Online ahead of print.

ABSTRACT

Previous studies in nephrotic syndrome have shown that three common variants in the ABCB1 gene including, rs1128503, rs2032582, and rs1045642, change the expression and activity of ABCB1 that may be responsible for drug resistance. However, due to inconclusive outcomes of these studies, we performed a meta-analysis to validate the association between ABCB1 polymorphisms and the susceptibility of steroid-resistant nephrotic syndrome (SRNS). The association was evaluated by calculating the odds ratio (OR) and 95% confidence interval. All analyses were performed with Review Manager v5.4. A total of 12 studies containing 1,463 subjects (514 steroid-resistant and 949 steroid-sensitive) were included. SNP rs1128503 showed significant association with SRNS (p<0.05) only in the allele model (OR=1.40) in Africans. A statistically significant association was found for rs2032582 in codominant 2, dominant, recessive, and allele models (OR=1.85, 1.52, 1.38, and 1.34, respectively). Subgroup analysis revealed that rs2032582 showed a significant correlation with SRNS in codominant 1, 2, dominant, over-dominant, and allele model in Africans (OR=3.22, 3.52, 3.29, 1.74, and 1.83, respectively). In the case of rs1045642, codominant 1 (OR=0.72) and recessive model (OR=1.34) revealed a significant correlation with SRNS. Again, codominant 1 (OR=0.58), dominant (OR=0.69), and over-dominant model (OR=0.62) showed a protective effect in Asians. Haplotype analysis showed that TGC haplotype is associated with 1.83, 1.77, and 2.17 time significant correlation in overall, Asian, and African population, respectively. In contrast, CGC haplotype showed 0.69 and 0.57 time lower association in the overall and African populations, respectively. CTC haplotype also showed 1.79 time enhanced susceptibility for SRNS in the overall population. Our study suggests that ABCB1 polymorphisms are associated with SRNS development, especially in Africans and Asians.

PMID:35697639 | DOI:10.1002/jgm.3436

Child Adolesc Psychiatr Clin N Am. 2022 Jul;31(3):393-416. doi: 10.1016/j.chc.2022.03.003. Epub 2022 May 11.

ABSTRACT

The psychostimulants-amphetamine and methylphenidate-have been in clinical use for well more than 60 years. In general, both stimulants are rapidly absorbed with relatively poor bioavailability and short half-lives. The pharmacokinetics of both stimulants are generally linear and dose proportional although substantial interindividual variability in pharmacokinetics is in evidence. Amphetamine (AMP) is highly metabolized by several oxidative enzymes forming multiple metabolites while methylphenidate (MPH) is primarily metabolized by hydrolysis to the inactive metabolite ritalinic acid. At present, pharmacogenomic testing as an aid to guide dosing and personalized treatment cannot be recommended for either agent. Few pharmacokinetically based drug-drug interactions (DDIs) have been documented for either stimulant.

PMID:35697392 | DOI:10.1016/j.chc.2022.03.003

Front Pharmacol. 2022 May 20;13:928527. doi: 10.3389/fphar.2022.928527. eCollection 2022.

NO ABSTRACT

PMID:35694262 | PMC:PMC9175562 | DOI:10.3389/fphar.2022.928527

Pharmgenomics Pers Med. 2022 Jun 4;15:561-571. doi: 10.2147/PGPM.S363058. eCollection 2022.

ABSTRACT

BACKGROUND: Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics.

METHOD: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction.

RESULTS: The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients.

CONCLUSION: The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

PMID:35693129 | PMC:PMC9176238 | DOI:10.2147/PGPM.S363058