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Pharmacological Research Apr 2023Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the...
Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the roles of OATP2B1 in physiology and pharmacology, we established and characterized Oatp2b1 knockout (single Slco2b1 and combination Slco1a/1b/2b1) and humanized hepatic and intestinal OATP2B1 transgenic mouse models. While viable and fertile, these strains exhibited a modestly increased body weight. In males, unconjugated bilirubin levels were markedly reduced in Slco2b1 compared to wild-type mice, whereas bilirubin monoglucuronide levels were modestly increased in Slco1a/1b/2b1 compared to Slco1a/1b mice. Single Slco2b1 mice showed no significant changes in oral pharmacokinetics of several tested drugs. However, markedly higher or lower plasma exposure of pravastatin and the erlotinib metabolite OSI-420, respectively, were found in Slco1a/1b/2b1 compared to Slco1a/1b mice, while oral rosuvastatin and fluvastatin behaved similarly between the strains. In males, humanized OATP2B1 strains showed lower conjugated and unconjugated bilirubin levels than control Slco1a/1b/2b1-deficient mice. Moreover, hepatic expression of human OATP2B1 partially or completely rescued the impaired hepatic uptake of OSI-420, rosuvastatin, pravastatin, and fluvastatin in Slco1a/1b/2b1 mice, establishing an important role in hepatic uptake. Expression of human OATP2B1 in the intestine was basolateral and markedly reduced the oral availability of rosuvastatin and pravastatin, but not of OSI-420 and fluvastatin. Neither lack of Oatp2b1, nor overexpression of human OATP2B1 had any effect on fexofenadine oral pharmacokinetics. While these mouse models still have limitations for human translation, with additional work we expect they will provide powerful tools to further understand the physiological and pharmacological roles of OATP2B1.
Topics: Male; Mice; Humans; Animals; Bilirubin; Rosuvastatin Calcium; Fluvastatin; Pravastatin; Organic Anion Transporters; Mice, Transgenic; Peptides; Anions; Mice, Knockout
PubMed: 36907287
DOI: 10.1016/j.phrs.2023.106724 -
Clinical Pharmacokinetics Apr 2023Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our...
Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.
BACKGROUND AND OBJECTIVE
Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator.
METHODS
In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters.
RESULTS
In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone.
CONCLUSION
Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.
Topics: Adult; Humans; Rifampin; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Atorvastatin; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins; Pharmaceutical Preparations; Drug Interactions; Cytochrome P-450 Enzyme System; Membrane Transport Proteins; Cytochrome P-450 CYP3A Inhibitors; Organic Anion Transporters
PubMed: 36906733
DOI: 10.1007/s40262-023-01214-w -
IBRO Neuroscience Reports Jun 2023Pravastatin sodium is reported to have multiple beneficial effects in cerebral atherosclerosis and neuronal injury; however, the preventive effects on cerebral venous...
OBJECTIVES
Pravastatin sodium is reported to have multiple beneficial effects in cerebral atherosclerosis and neuronal injury; however, the preventive effects on cerebral venous ischemia are still unknown. Herein, we aimed to examine the neuroprotective effects of transoral prior administration of pravastatin sodium against cerebral cortical venous ischemia with suppression of apoptosis.
METHODS
Thirty 8-week-old male Wistar rats were divided equally into two study groups (n = 15 vs. n = 15); the pravastatin group was fed 1% pravastatin sodium with their usual diet for 2 weeks, while the control group only received the usual diet. Two-vein occlusion (2VO) model was applied for this study, and two adjacent cortical veins in each animal were permanently occluded photochemically with rose bengal dye. During photo-thrombosis, regional changes of the cerebral blood flow (CBF) in area of the venous ischemia were recorded. At 48-h after 2VO, animals were euthanized using perfusion fixation, and we histologically measured ratios of infarcted area to contralateral hemisphere, and counted Bax- and Bcl-2-positive cells in the penumbra to investigate the implications for apoptosis.
RESULTS
The ratio of infarcted area was significantly decreased in the pravastatin group compared to the control group (P < 0.01). The number of Bax-positive cells also decreased significantly in the pravastatin group (P < 0.01). In contrast, immunolabeling for Bcl-2 was essentially negative in all areas in both groups. There were also no significant differences in regional CBF changes after 2VO between the two groups (P = 0.13).
CONCLUSIONS
Pre-emptive administration of pravastatin sodium mixed in the food has neuroprotective effects against cerebral cortical venous ischemia with suppression of apoptosis associated with inhibition of Bax expression but has little influence on regional CBF.
PubMed: 36852215
DOI: 10.1016/j.ibneur.2023.02.002 -
Frontiers in Medicine 2023Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus...
Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants' response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.
PubMed: 36844201
DOI: 10.3389/fmed.2023.1122529 -
International Journal of Nanomedicine 2023Pravastatin sodium (PVS) is a hypolipidemic drug which suffers from extensive first-pass metabolism and short half-life. Poly(d,l-lactide--glycolide) (PLGA) is...
PURPOSE
Pravastatin sodium (PVS) is a hypolipidemic drug which suffers from extensive first-pass metabolism and short half-life. Poly(d,l-lactide--glycolide) (PLGA) is considered a promising carrier to improve its hypolipidemic and hepatoprotective activities.
METHODS
PVS-loaded PLGA nanoparticles (PVS-PLGA-NPs) were prepared by double emulsion method using a full 3 factorial design. The in vitro release and the physical stability studies of the optimized PVS-PLGA-NPs (F5) were performed. Finally, both hypolipidemic and hepatoprotective activities of the optimized F5 NPs were studied and compared to PVS solution.
RESULTS
All the studied physical parameters of the prepared NPs were found in the accepted range. The particle size (PS) ranged from 90 ± 0.125 nm to 179.33 ± 4.509 nm, the poly dispersity index (PDI) ranged from 0.121 ± 0.018 to 0.158 ± 0.014. The optimized NPs (F5) have the highest entrapment efficiency (EE%) (51.7 ± 5%), reasonable PS (168.4 ± 2.506 nm) as well as reasonable zeta potential (ZP) (-28.3 ± 1.18mv). Solid-state characterization indicated that PVS is well entrapped into NPs. All NPs have distinct spherical shape with smooth surface. The prepared NPs showed a controlled release profile. F5 showed good stability at 4 ± 2°C during the whole storage period of 3 months. In vivo study and histopathological examination indicated that F5 NPs showed significant increase in PVS hypolipidemic as well as hepatoprotective activity compared to PVS solution.
CONCLUSION
The PVS-PLGA-NPs could be considered a promising model to evade the first-pass effect and showed improvement in the hypolipidemic and hepatoprotective activities compared to PVS solution.
Topics: Polylactic Acid-Polyglycolic Acid Copolymer; Lactic Acid; Polyglycolic Acid; Drug Carriers; Pravastatin; Nanoparticles; Particle Size
PubMed: 36816332
DOI: 10.2147/IJN.S394701 -
The American Journal of Case Reports Feb 2023BACKGROUND Comorbidities and polypharmacy are difficult to manage, as polypharmacy hinders identification and prevention of medication-related problems. Risk for adverse...
BACKGROUND Comorbidities and polypharmacy are difficult to manage, as polypharmacy hinders identification and prevention of medication-related problems. Risk for adverse drug events (ADEs) can be minimized through pharmacogenomic (PGx) testing and related therapeutic adjustments. CASE REPORT A 70-year-old woman with comorbidities and medications enrolled in the Program of All-inclusive Care for the Elderly presented with left lower extremity (LLE) pain, generalized weakness, and major depressive disorder. The provider requested a medication safety review, where the clinical pharmacist-recommended PGx testing given the LLE pain and weakness while taking a statin and inconsistent INR readings taking warfarin. The pharmacist recommended switching atorvastatin to pravastatin to minimize the risk for statin-associated ADEs due to CYP3A4 inhibition and switching fluoxetine to citalopram due to uncontrolled depression/anxiety and to mitigate drug-drug interactions with carvedilol to reduce the risk of orthostatic hypotension. Recommendations were accepted and upon follow-up the patient reported minor LLE pain and improved wellbeing on citalopram. Following PGx testing, the patient had decreased function at SLCO1B1 and was an intermediate metabolizer for CYP2C9 and CYP2D6. This case demonstrates how preemptive PGx testing would have identified drug-gene interactions (DGIs) at the time of prescribing and reduced the risk of statin-associated muscular symptoms, highlighting the utility of panel-based PGx testing in older adults at high risk for ADEs and/or therapy failure. CONCLUSIONS Decreased function at SLCO1B1 increases exposure to statins, leading to statin-induced myalgias, as displayed in this case. PGx testing can help identify DGIs, choose optimal therapies in medically complex older adults, and minimize ADE risk.
Topics: Aged; Female; Humans; Citalopram; Depressive Disorder, Major; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Pain; Pharmacogenomic Testing; Polypharmacy
PubMed: 36804920
DOI: 10.12659/AJCR.938850 -
Journal of Clinical Hypertension... Mar 2023Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to... (Meta-Analysis)
Meta-Analysis
Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti-hypertensive. Using a meta-analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002-2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was -1.42 (95% CI: -2.38, -0.46; p = .004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: -1.28, -0.36; p = .0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non-significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi-ethnic, large sample pool size, and a long period follow-up study is still required to assert these claims.
Topics: Humans; Blood Pressure; Hypertension; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Randomized Controlled Trials as Topic; Antihypertensive Agents; Multicenter Studies as Topic
PubMed: 36799888
DOI: 10.1111/jch.14645 -
Plants (Basel, Switzerland) Jan 2023Herb-drug interactions are nowadays an important decision factor in many healthcare interventions. Patients with cardiovascular risk factors such as hyperlipidemia and... (Review)
Review
BACKGROUND
Herb-drug interactions are nowadays an important decision factor in many healthcare interventions. Patients with cardiovascular risk factors such as hyperlipidemia and hypertension are usually prescribed long-term treatments. We need more informed decision tools to direct future clinical research and decision making to avoid HDI occurrences in this group.
METHODS
A scoping review was conducted using data from online databases such as PUBMED, the National Library of Medicine, and the electronic Medicines Compendium. Included studies consisted of the reported effects on Phase 1/2 and P-glycoprotein of herbal medicines listed in the medicines agencies of Latin America and Europe and drugs used for cardiovascular conditions (statins, diuretics, beta blockers, calcium channel blockers, and ACE inhibitors). The cross tabulation of the results allowed for finding potential HDI.
RESULTS AND CONCLUSIONS
as per the preclinical data reviewed here, we encourage more clinical research on whether drugs with apparently very low interaction risk, such as pravastatin, nadolol, and nimodipine/nitrendipine, may help prevent HDI when statins, beta blockers, and calcium channel blockers, respectively, are prescribed for long-term treatments.
PubMed: 36771707
DOI: 10.3390/plants12030623 -
European Journal of Obstetrics,... Apr 2023Preeclampsia (PE) is the major cause of maternal morbidity and mortality and the leading cause of premature delivery worldwide. As well as intrauterine growth...
OBJECTIVE
Preeclampsia (PE) is the major cause of maternal morbidity and mortality and the leading cause of premature delivery worldwide. As well as intrauterine growth restriction (IUGR), PE is associated with pathogenic evidence of placental malperfusion and ischemia. Recent literature has highlighted the potential of pravastatin in the prevention and treatment of these conditions. Aim of this study is to describe perinatal outcomes and placental histopathological findings in a small series of pregnant women with severe PE and IUGR treated with pravastatin on compassionate grounds. Two-year follow up of these babies is provided.
STUDY DESIGN
Between October 2017 and October 2019 in Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy, women with singleton pregnancy between 19.6 and 27.6 gestational weeks, who presented with severe PE and IUGR were counselled for a compassionate treatment with Pravastatin 40 mg a day. Treated women were compared with controls identified with similar data in terms of gestational age at diagnosis, clinical maternal data, Doppler severity findings. Neonates were followed up for two years.
RESULTS
The median time from diagnosis to delivery was 39 days (IQR 20) for women in the pravastatin group and 20 days (IQR 20.5) for controls. Looking to maternal blood exams, in the group of women treated with pravastatin, maximum transaminase, creatinine levels were lower than in controls, where the minimum platelet count was higher. Placenta examination did not reveal any significant differences in placental histopathological findings. No significant differences were observed in the investigated perinatal data, as well as in infant follow-up, although an increased prenatal weight gain was found in treated pregnancies in comparison to controls.
CONCLUSIONS
Our data did not allow us to find significant differences in pregnancy outcome and infant follow-up, as well as in placental histological picture in preeclamptic patients when pravastatin is administered in the late second trimester. However, we suggest its possible role in stabilizing the disease, increasing the prenatal weight gain and prolonging the duration of pregnancy, thus preventing the progression to a more severe maternal disease.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Infant; Pravastatin; Pre-Eclampsia; Placenta; Follow-Up Studies; Pregnancy Outcome; Fetal Growth Retardation
PubMed: 36764034
DOI: 10.1016/j.ejogrb.2023.01.036