Efflux and uptake transporters as determinants of statin response

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

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Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Cells ◽

10.3390/cells10030709 ◽

2021 ◽

Vol 10 (3) ◽

pp. 709

Author(s):

Bradley M. Roberts ◽

Emanuel F. Lopes ◽

Stephanie J. Cragg

Keyword(s):

Gabab Receptors ◽

Striatal Dopamine ◽

Aminobutyric Acid ◽

Gaba Uptake ◽

Short Term Plasticity ◽

Psychomotor Disorders ◽

Gabaa And Gabab Receptors ◽

Uptake Transporters ◽

Gabaergic Modulation ◽

Da Release

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

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Variants Near CETP, MTTP and BUD13-ZPR1-APOA5 may be Nominally Associated with Poor Statin Response Among Filipinos

Acta Medica Philippina ◽

10.47895/amp.vi0.2353 ◽

2021 ◽

Keyword(s):

Statin Response

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Lack of Association of KIF6 Genotype With Vascular Disease and Statin Response

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.111.960955 ◽

2011 ◽

Vol 4 (4) ◽

pp. 467-468 ◽

Cited By ~ 2

Author(s):

Kiran Musunuru

Keyword(s):

Vascular Disease ◽

Statin Response

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Abstract 531: Is Earlier Hepatitis A Associated with Abnormal Hepatic Response to Statin Therapy?

Circulation ◽

10.1161/circ.116.suppl_16.ii_94 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Helmut Sinzinger ◽

Simona Marchesi ◽

Graziana Lupattelli

Keyword(s):

Side Effects ◽

Alcohol Abuse ◽

Statin Therapy ◽

Hepatic Steatosis ◽

Hepatitis A ◽

Hepatic Enzyme ◽

Steatosis Hepatis ◽

Enzyme Elevation ◽

Drug Free ◽

Statin Response

Hepatic enzyme elevation is low (< 3%) in large statin trials. Elevations are reversible after dose reduction or statin withdrawal. Very rare cases of hepatitis have been reported. No data are available how predisposing risk factors /diseases might influence hepatic statin response. Among the patients suffering from hepatic side effects during statin therapy 896 (477 m, 419 f; aged 31–76 years) admitted with (one or more) elevated hepatic enzyme, anamnestic data on hepatitis A, B, C, hepatic steatosis, alcohol abuse, hepatobiliary problems, abnormal enzymes (GOT, GPT, γGT) were assessed. The prevalence (% vs. % statin use in Austria) was for lovastatin n= 4; 0,2 (0,7), fluvastatin n = 111; 12,4 (14,0), simvastatin n = 297; 33,1 (34,8), pravastatin n = 82; 9,2 (11,8), rosuvastatin n = 69; 7,9 (1,5), atorvastatin n = 333; 37,2 (37,2). Only 41 patients (4,27%) had concomitant muscle complaints (21 cramps, 16 aches, 3 stiffness, 1 weakness), 12 (1,33%) CK elevation, 261 (29,13%) elevated isoprostane 8epiPGF 2α . Those with muscle complaints had normal CK levels and vice versa. Pretherapeutic findings (more than one possible) were hepatitis A 326 (36,4% !!), hepatitis B 7 (0,8%), hepatitis C 3 (0,3%), hepatic steatosis 141 (15,7%), alcohol abuse 104 (11,6%) and /or hepatobiliary problems 17 (1,9%). Abnormal enzymes GOT 116 (12,9%), GPT 113 (12,6%), γGT 147 (16,4%) persisted for < 1 week. Patients after hepatitis A had significantly (p < 0,001) higher transaminases as compared to the other patients. Withdrawal of the respective statin normalized transaminases within 4 weeks in 129 patients (14,4%), in only 7 elevation persisted for a longer period (up to 7 months). After 1 year all were in the normal range. Transaminase levels due to steatosis hepatis even sometimes showed improvement after statin therapy (mean: −12,7% GOT; −14,1 GPT; −16,0 γGT). Reexposure to another statin compound after a 4 weeks drug free interval caused recurrence of side effects in 87 patients (49 with earlier hepatitis A = 56,3%). Hepatitis A seems to represent a high risk for abnormal liver function response on statin therapy and reexposure to other compounds of this family. The combination of abnormal hepatic response with muscle complaints is very rare.

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Abstract 16278: Discordant Lipid Phenotype and Other Determinants of Statin Response in the Pravastatin Inflammation/crp Evaluation (PRINCE) Trial

Circulation ◽

10.1161/circ.142.suppl_3.16278 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Oluremi N Ajala ◽

Olga Demler ◽

Yanyan Liu ◽

Paul M Ridker ◽

Robert J Glynn ◽

...

Keyword(s):

Moderate Intensity ◽

Forward Selection ◽

Cvd Risk ◽

Double Blind ◽

Apo B ◽

Lipid Phenotype ◽

Validation Of Models ◽

Baseline Levels ◽

Hs Crp ◽

Statin Response

Introduction: Wide variability in LDL-C change is observed with statins, yet determinants of statin response are uncertain. Methods: Participants were selected from the primary prevention cohort of the Pravastatin Inflammation/CRP Evaluation double-blind trial that randomized participants to pravastatin 40 mg/d or placebo over 24 weeks. Baseline and 24-week levels of LDL-C and 15 other biomarkers were measured in 495 participants. We defined optimal statin response as >=30% LDL-C reduction and suboptimal response as <30% reduction. Sub-optimal hs-CRP response was defined as >=median (14%) decline in hs-CRP from baseline to 24 weeks and non-response as no decrease or an increase in hs-CRP. χ 2 , t-tests and ANOVA were used to compare variables across optimal statin response (N=166) and suboptimal response (N=287). Multivariable logistic regression models evaluated associations of determinants of statin response. Forward selection identified variables that associated with response. Xgboost was used to train and validate the models using 2/3 and 1/3 of the data respectively. Results: Significant determinants of optimal statin response included older age, and higher baseline levels of LDL-C and triglyceride-rich lipoproteins. By contrast, female sex, alcohol intake >=1 drink/day, diabetes, higher baseline levels of apo B and lipoprotein(a) were associated with decreased response, as was hs-CRP non-response (Table). Race, baseline hs-CRP and sub-optimal hs-CRP response, smoking, HDL-C and BMI had no significant effect on statin LDL-C response. Training and validation of models predicted suboptimal LDL-C response with an AUC of 0.71. Similarly, training and validation of models using Xgboost yielded an AUC of 0.85. Conclusion: This study identified discordant lipid phenotype and other determinants of moderate-intensity statin response and suggests other pathways of CVD risk beyond those addressed by statin treatment that require further investigation.

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