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Journal of Clinical Medicine Apr 2024: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the...
: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). : A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and , and SNP while on two different dabigatran doses (110 and 150 mg BID). : A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different and genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the heterozygous genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype ( = 0.048). In patients with the genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 ( = 0.042). : heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.
PubMed: 38731074
DOI: 10.3390/jcm13092545 -
Cancers Apr 2024The blood-brain barrier is composed of both a physical barrier and an enzymatic barrier. Tight junction (TJ) proteins expressed between endothelial cells of brain...
The blood-brain barrier is composed of both a physical barrier and an enzymatic barrier. Tight junction (TJ) proteins expressed between endothelial cells of brain capillaries provide the physical barrier to paracellular movement of ions and molecules to the brain, while luminal-facing efflux transporters enzymatically restrict the entry of blood-borne molecules from entering the brain. The expression and activity of ATP Binding Cassette transporters or "ABC" transporters in endothelial cells of the BBB and in human tumor cells are dynamically regulated by numerous signaling pathways. P-glycoprotein (P-gp), (ABCB1), is arguably the most studied transporter of the BBB, and in human cell lines. P-glycoprotein transport activity is rapidly inhibited by signaling pathways that call for the rapid production of nitric oxide (NO) from the inducible nitric oxide synthase enzyme, iNOS. This study investigated how nano-molar levels of the selective chemotherapeutic erastin affect the activity or expression of P-glycoprotein transporter in brain capillaries and in human tumor cell lines. We chose erastin because it signals to iNOS for NO production at low concentrations. Furthermore, erastin inhibits the cellular uptake of cystine through the X cystine/glutamate antiporter. Since previous reports indicate that NO production from iNOS can rapidly inhibit P-gp activity in tumor cells, we wondered if induction of iNOS by erastin could also rapidly reduce P-glycoprotein transport activity in brain endothelial cells and in human tumor cell lines. We show here that low concentrations of erastin (1 nM) can induce iNOS, inhibit the activity of P-glycoprotein, and reduce the intracellular uptake of cystine via the Xc- cystine/glutamate antiporter. Consistent with reduced P-glycoprotein activity in rat brain capillary endothelial cells, we show that human tumor cell lines exposed to erastin become more sensitive to cytotoxic substrates of P-glycoprotein.
PubMed: 38730685
DOI: 10.3390/cancers16091733 -
In Silico Pharmacology 2024Genes related to MAPK-ERK signaling pathways, and epithelial-mesenchymal transition induction is evolutionarily conserved and has crucial roles in the regulation of...
UNLABELLED
Genes related to MAPK-ERK signaling pathways, and epithelial-mesenchymal transition induction is evolutionarily conserved and has crucial roles in the regulation of important cellular processes, including cell proliferation. In this study, six cannabinoids from were docked with MAPK-ERK signaling pathways to identify their possible binding interactions. The results showed that all the cannabinoids have good binding affinities with the target proteins. The best binding affinities were MEK- tetrahydrocannabinol (- 8.8 kcal/mol) and P13k-cannabinol (- 8.5 kcal/mol). The root mean square deviation was calculated and used two alternative variants (rmsd/ub and rmsd/lb) and the values of rmsd/lb fluctuated 8.6-2.0 Å and for rmsd/ub from 1.0 to 2.0 Å that suggests the cannabinoids and protein complex are accurate and cannot destroy on binding. The study analyzed the pharmacokinetic and drug-likeness properties of six cannabinoids from leaves using the SwissADME web tool. Lipinski's rule of five was used to predict drug-likeness and showed that all compounds have not violated it and the total polar surface area of cannabinoids was also according to Lipinski's rule that is benchmarked of anticancer drugs. Cannabinoids are meet the requirements of leadlikeness and synthetic accessibility values showed they can be synthesized. The molecular weight, XLOGP3, solubility (log S), and flexibility (FLEX) are according to the bioavailability radar. The bioavailability score and consensus Log Po/w fall within the acceptable range for the suitable drug. Pharmacokinetics parameters showed that cannabinoids cannot cross the blood-brain barrier, have high GI absorption as well as cannabinoids are substrates of (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) but no substrate of P-glycoprotein. Based on these findings, the study suggests that cannabinoids are suitable drugs that could be used as effective inhibitors for target proteins involved in cancer pathways. Among the six cannabinoids, cannabinol and tetrahydrocannabinol exerted maximum binding affinities with proteins of MAPK-ERK signaling pathways, and their pharmacokinetics and drug-likeness-related profiles suggest that these cannabinoids could be superlative inhibitors in cancer treatment. Further in vitro, in vivo, and clinical studies are needed to explore their potential in cancer treatment.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40203-024-00213-4.
PubMed: 38716440
DOI: 10.1007/s40203-024-00213-4 -
Fluids and Barriers of the CNS May 2024Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim...
BACKGROUND
Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H/OC) antiporter. Additionally, we evaluated whether triptans interacted with the efflux transporter, P-glycoprotein (P-gp).
METHODS
We investigated the cellular uptake characteristics of the prototypical H/OC antiporter substrates, pyrilamine and oxycodone, and seven different triptans in the human brain microvascular endothelial cell line, hCMEC/D3. Triptan interactions with P-gp were studied using the IPEC-J2 MDR1 cell line. Lastly, in vivo neuropharmacokinetic assessment of the unbound brain-to-plasma disposition of eletriptan was conducted in wild type and mdr1a/1b knockout mice.
RESULTS
We demonstrated that most triptans were able to inhibit uptake of the H/OC antiporter substrate, pyrilamine, with eletriptan emerging as the strongest inhibitor. Eletriptan, almotriptan, and sumatriptan exhibited a pH-dependent uptake into hCMEC/D3 cells. Eletriptan demonstrated saturable uptake kinetics with an apparent K of 89 ± 38 µM and a J of 2.2 ± 0.7 nmol·min·mg protein (n = 3). Bidirectional transport experiments across IPEC-J2 MDR1 monolayers showed that eletriptan is transported by P-gp, thus indicating that eletriptan is both a substrate of the H/OC antiporter and P-gp. This was further confirmed in vivo, where the unbound brain-to-unbound plasma concentration ratio (K) was 0.04 in wild type mice while the ratio rose to 1.32 in mdr1a/1b knockout mice.
CONCLUSIONS
We have demonstrated that the triptan family of compounds possesses affinity for the H/OC antiporter proposing that the putative H/OC antiporter plays a role in the BBB transport of triptans, particularly eletriptan. Our in vivo studies indicate that eletriptan is subjected to simultaneous brain uptake and efflux, possibly facilitated by the putative H/OC antiporter and P-gp, respectively. Our findings offer novel insights into the potential central site of action involved in migraine treatment with triptans and highlight the significance of potential transporter related drug-drug interactions.
Topics: Tryptamines; Animals; Endothelial Cells; Humans; Mice, Knockout; Blood-Brain Barrier; Brain; Cell Line; Mice; Mice, Inbred C57BL; Biological Transport; ATP Binding Cassette Transporter, Subfamily B, Member 1; Male; Antiporters; Pyrilamine; ATP Binding Cassette Transporter, Subfamily B; Pyrrolidines
PubMed: 38711118
DOI: 10.1186/s12987-024-00544-6 -
Clinical and Translational Science May 2024St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and...
St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.
Topics: Humans; Hypericum; Blood-Brain Barrier; Phloroglucinol; Plant Extracts; Male; Adult; Positron-Emission Tomography; Terpenes; Female; Young Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds; Terfenadine; Cytochrome P-450 Enzyme System; Healthy Volunteers
PubMed: 38700454
DOI: 10.1111/cts.13804 -
Frontiers in Pharmacology 2024[This corrects the article DOI: 10.3389/fphar.2022.795613.].
[This corrects the article DOI: 10.3389/fphar.2022.795613.].
PubMed: 38698815
DOI: 10.3389/fphar.2024.1363218 -
The Journal of International Medical... May 2024Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19)....
Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.
Topics: Humans; Ritonavir; Tacrolimus; Drug Interactions; Male; Middle Aged; COVID-19 Drug Treatment; Kidney Transplantation; SARS-CoV-2; Female; Hematopoietic Stem Cell Transplantation; Immunosuppressive Agents; Cytochrome P-450 CYP3A Inhibitors; Drug Combinations; COVID-19; Aged; Antiviral Agents
PubMed: 38698526
DOI: 10.1177/03000605241247705 -
Scientific Reports Apr 2024Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to...
Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88-1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.
Topics: Humans; Atrial Fibrillation; Male; Female; Aged, 80 and over; Gastrointestinal Hemorrhage; Registries; Aged; Anticoagulants; Risk Factors; Incidence; Warfarin
PubMed: 38678096
DOI: 10.1038/s41598-024-59932-5 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the...
Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base () was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC < 20 μM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with ICs of 0.45 and 12.1 μM, respectively.
PubMed: 38675499
DOI: 10.3390/ph17040539 -
Genes Apr 2024Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is...
Association of CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T Polymorphisms with Tacrolimus Dose, Serum Concentration, and Biochemical Parameters in Mexican Patients with Kidney Transplant.
UNLABELLED
Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, particularly CYP3A4 and CYP3A5. Several single-nucleotide polymorphisms (SNPs) have been identified in the genes encoding , , and , including CYP3A4-392A/G (rs2740574), CYP3A5 6986A/G (rs776746), and ABCB1 3435C/T (rs1045642). This study aims to evaluate the association among CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T polymorphisms and TAC, serum concentration, and biochemical parameters that may affect TAC pharmacokinetics in Mexican kidney transplant (KT) patients.
METHODS
Forty-six kidney transplant recipients (KTR) receiving immunosuppressive treatment with TAC in different combinations were included. CYP3A4, CYP3A5, and gene polymorphisms were genotyped using qPCR TaqMan. Serum TAC concentration (as measured) and intervening variables were assessed. Logistic regression analyses were performed at baseline and after one month to assess the extent of the association between the polymorphisms, intervening variables, and TAC concentration.
RESULTS
The GG genotype of CYP3A5-6986 A/G polymorphism is associated with TAC pharmacokinetic variability OR 4.35 (95%CI: 1.13-21.9; = 0.0458) at one month of evolution; in multivariate logistic regression, CYP3A5-6986GG genotype OR 9.32 (95%CI: 1.54-93.08; = 0.028) and the use of medications or drugs that increase serum TAC concentration OR 9.52 (95%CI: 1.79-88.23; = 0.018) were strongly associated with TAC pharmacokinetic variability.
CONCLUSION
The findings of this study of the Mexican population showed that CYP3A5-6986 A/G GG genotype is associated with a four-fold increase in the likelihood of encountering a TAC concentration of more than 15 ng/dL. The co-occurrence of the CYP3A5-6986GG genotype and the use of drugs that increase TAC concentration correlates with a nine-fold increased risk of experiencing a TAC at a level above 15 ng/mL. Therefore, these patients have an increased susceptibility to TAC-associated toxicity.
Topics: Humans; Cytochrome P-450 CYP3A; Kidney Transplantation; Tacrolimus; ATP Binding Cassette Transporter, Subfamily B; Female; Male; Polymorphism, Single Nucleotide; Adult; Mexico; Immunosuppressive Agents; Middle Aged; Genotype; Graft Rejection
PubMed: 38674430
DOI: 10.3390/genes15040497