Machine Learning Exploration of the Relationship Between Drugs and the Blood-Brain Barrier: Guiding Molecular Modification.

OBJECTIVE: This study aimed to improve the efficiency of pharmacotherapy for CNS diseases by optimizing the ability of drug molecules to penetrate the Blood-Brain Barrier (BBB). METHODS: We established qualitative and quantitative databases of the ADME properties of drugs and derived characteristic features of compounds with efficient BBB penetration. Using these insights, we developed four machine learning models to predict a drug's BBB permeability by assessing ADME properties and molecular topology. We then validated the models using the B3DB database. For acyclovir and ceftriaxone, we modified the Hydrogen Bond Donors and Acceptors, and evaluated the BBB permeability using the predictive model. RESULTS: The machine learning models performed well in predicting BBB permeability on both internal and external validation sets. Reducing the number of Hydrogen Bond Donors and Acceptors generally improves BBB permeability. Modification only enhanced BBB penetration in the case of acyclovir and not ceftriaxone. CONCLUSIONS: The machine learning models developed can accurately predict BBB permeability, and many drug molecules are likely to have increased BBB penetration if the number of Hydrogen Bond Donors and Acceptors are reduced. These findings suggest that molecular modifications can enhance the efficacy of CNS drugs and provide practical strategies for drug design and development. This is particularly relevant for improving drug penetration of the BBB.

An In Silico Explainable Multiparameter Optimization Approach for De Novo Drug Design against Proteins from the Central Nervous System.

The aim of drug design and development is to produce a drug that can inhibit the target protein and possess a balanced physicochemical and toxicity profile. Traditionally, this is a multistep process where different parameters such as activity and physicochemical and pharmacokinetic properties are optimized sequentially, which often leads to high attrition rate during later stages of drug design and development. We have developed a deep learning-based de novo drug design method that can design novel small molecules by optimizing target specificity as well as multiple parameters (including late-stage parameters) in a single step. All possible combinations of parameters were optimized to understand the effect of each parameter over the other parameters. An explainable predictive model was used to identify the molecular fragments responsible for the property being optimized. The proposed method was applied against the human 5-hydroxy tryptamine receptor 1B (5-HT1B), a protein from the central nervous system (CNS). Various physicochemical properties specific to CNS drugs were considered along with the target specificity and blood-brain barrier permeability (BBBP), which act as an additional challenge for CNS drug delivery. The contribution of each parameter toward molecule design was identified by analyzing the properties of generated small molecules from optimization of all possible parameter combinations. The final optimized generative model was able to design similar inhibitors compared to known inhibitors of 5-HT1B. In addition, the functional groups of the generated small molecules that guide the BBBP predictive model were identified through feature attribution techniques.

Brain Distribution of Drugs: Pharmacokinetic Considerations.

It is crucial to understand the basic principles of drug transport, from the site of delivery to the site of action within the CNS, in order to evaluate the possible utility of a new drug candidate for CNS action, or possible CNS side effects of non-CNS targeting drugs. This includes pharmacokinetic aspects of drug concentration-time profiles in plasma and brain, blood-brain barrier transport and drug distribution within the brain parenchyma as well as elimination processes from the brain. Knowledge of anatomical and physiological aspects connected with drug delivery is crucial in this context. The chapter is intended for professionals working in the field of CNS drug development and summarizes key pharmacokinetic principles and state-of-the-art experimental methodologies to assess brain drug disposition. Key parameters, describing the extent of unbound (free) drug across brain barriers, in particular blood-brain and blood-cerebrospinal fluid barriers, are presented along with their application in drug development. Special emphasis is given to brain intracellular pharmacokinetics and its role in evaluating target engagement. Fundamental neuropharmacokinetic differences between small molecular drugs and biologicals are discussed and critical knowledge gaps are outlined.

Screening novel CNS drug candidates for P-glycoprotein interactions using the cell line iP-gp: In vitro efflux ratios from iP-gp and MDCK-MDR1 monolayers compared to brain distribution data from mice.

Drug efflux by P-glycoprotein (P-gp, ABCB1) is considered as a major obstacle for brain drug delivery for small molecules. P-gp-expressing cell monolayers are used for screening of new drug candidates during early states of drug development. It is, however, uncertain how well the in vitro studies can predict the in vivo P-gp mediated efflux at the blood-brain barrier (BBB). We previously developed a novel cell line of porcine origin, the iP-gp cell line, with high transepithelial resistance and functional expression of human P-gp. The aim of the present study was to evaluate the applicability of the cell line for screening of P-gp interactions of novel drug candidates. For this purpose, bidirectional fluxes of 14 drug candidates were measured in iP-gp cells and in MDCK-MDR1 cells, and compared with pharmacokinetic data obtained in male C57BL/6 mice. The iP-gp cells formed extremely tight monolayers (>15 000 Ω∙cm2) as compared to the MDCK- MDR1 cells (>250 Ω∙cm2) and displayed lower Papp,a-b values. The efflux ratios obtained with iP-gp and MDCK-MDR1 monolayers correlated with Kp,uu,brain values from the in vivo studies, where compounds with the lowest Kp,uu,brain generally displayed the highest efflux ratios. 12 of the tested compounds displayed a poor BBB penetration in mice as judged by Kp,uu less than 1. Of these compounds, nine compounds were categorized as P-gp substrates in the iP-gp screening, whereas analysis of data estimated in MDCK-MDR1 cells indicated four compounds as potential substrates. The results suggest that the iP-gp cell model may be a sensitive and useful screening tool for drug screening purposes to identify possible substrates of human P-glycoprotein.

Multifunctional Arylsulfone and Arylsulfonamide-Based Ligands with Prominent Mood-Modulating Activity and Benign Safety Profile, Targeting Neuropsychiatric Symptoms of Dementia.

The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT2A/6/7 and D2 receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg), outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding comparator anxiolytics. In contrast to the existing psychotropic agents tested, the novel chemotypes did not negatively impact cognition. At a chronic dose regimen (25 days), 11 did not induce significant metabolic or adverse blood pressure disturbances. These promising therapeutic-like activities and benign safety profiles make the novel chemotypes potential treatment options for dementia patients.

Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review.

Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabissativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics.

Strategies for delivering therapeutics across the blood-brain barrier.

Achieving sufficient delivery across the blood-brain barrier is a key challenge in the development of drugs to treat central nervous system (CNS) disorders. This is particularly the case for biopharmaceuticals such as monoclonal antibodies and enzyme replacement therapies, which are largely excluded from the brain following systemic administration. In recent years, increasing research efforts by pharmaceutical and biotechnology companies, academic institutions and public-private consortia have resulted in the evaluation of various technologies developed to deliver therapeutics to the CNS, some of which have entered clinical testing. Here we review recent developments and challenges related to selected blood-brain barrier-crossing strategies - with a focus on non-invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes - and analyse their potential in the treatment of CNS disorders.

The role of brain barriers in the neurokinetics and pharmacodynamics of lithium.

Lithium (Li) is the most widely used mood stabilizer in treating patients with bipolar disorder. However, more than half of the patients do not or partially respond to Li therapy, despite serum Li concentrations in the serum therapeutic range. The exact mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) relationships of lithium are still poorly understood and alteration in the brain pharmacokinetics of lithium may be one of the mechanisms explaining the variability in the clinical response to Li. Brain barriers such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a crucial role in controlling blood-to-brain and brain-to-blood exchanges of various molecules including central nervous system (CNS) drugs. Recent in vivo studies by nuclear resonance spectroscopy revealed heterogenous brain distribution of Li in human that were not always correlated with serum concentrations, suggesting regional and variable transport mechanisms of Li through the brain barriers. Moreover, alteration in the functionality and integrity of brain barriers is reported in various CNS diseases, as a cause or a consequence and in this regard, Li by itself is known to modulate BBB properties such as the expression and activity of various transporters, metabolizing enzymes, and the specialized tight junction proteins on BBB. In this review, we will focus on recent knowledge into the role of the brain barriers as key-element in the Li neuropharmacokinetics which might improve the understanding of PK-PD of Li and its interindividual variability in drug response.

Functional Investigation of Solute Carrier Family 35, Member F2, in Three Cellular Models of the Primate Blood-Brain Barrier.

Understanding the mechanisms of drug transport across the blood-brain barrier (BBB) is an important issue for regulating the pharmacokinetics of drugs in the central nervous system. In this study, we focused on solute carrier family 35, member F2 (SLC35F2), whose mRNA is highly expressed in the BBB. SLC35F2 protein was enriched in isolated mouse and monkey brain capillaries relative to brain homogenates and was localized exclusively on the apical membrane of MDCKII cells and brain microvascular endothelial cells (BMECs) differentiated from human induced pluripotent stem cells (hiPS-BMECs). SLC35F2 activity was assessed using its substrate, YM155, and pharmacological experiments revealed SLC35F2 inhibitors, such as famotidine (half-maximal inhibitory concentration, 160 µM). Uptake of YM155 was decreased by famotidine or SLC35F2 knockdown in immortalized human BMECs (human cerebral microvascular endothelial cell/D3 cells). Furthermore, famotidine significantly inhibited the apical (A)-to-basal (B) transport of YM155 in primary cultured monkey BMECs and hiPS-BMECs. Crucially, SLC35F2 knockout diminished the A-to-B transport and intracellular accumulation of YM155 in hiPS-BMECs. By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents. SIGNIFICANCE STATEMENT: This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system.

Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease.

Preclinical and clinical data support the use of focused ultrasound (FUS), in the presence of intravenously injected microbubbles, to safely and transiently increase the permeability of the blood-brain barrier (BBB). FUS-induced BBB permeability has been shown to enhance the bioavailability of administered intravenous therapeutics to the brain. Ideal therapeutics candidates for this mode of delivery are those capable of inducing benefits peripherally following intravenous injection and in the brain at FUS-targeted areas. In Alzheimer's disease, intravenous immunoglobulin (IVIg), a fractionated human blood product containing polyclonal antibodies, act as immunomodulator peripherally and centrally, and it can reduce amyloid pathology in the brain. Using the TgCRND8 mouse model of amyloidosis, we tested whether FUS can improve the delivery of IVIg, administered intravenously (0.4 g/kg), to the hippocampus and reach an effective dose to reduce amyloid plaque pathology and promote neurogenesis. Our results show that FUS-induced BBB permeability is required to deliver a significant amount of IVIg (489 ng/mg) to the targeted hippocampus of TgCRN8 mice. Two IVIg-FUS treatments, administered at days 1 and 8, significantly increased hippocampal neurogenesis by 4-, 3-, and 1.5-fold in comparison to saline, IVIg alone, and FUS alone, respectively. Amyloid plaque pathology was significantly reduced in all treatment groups: IVIg alone, FUS alone, and IVIg-FUS. Putative factors promoting neurogenesis in response to IVIg-FUS include the down-regulation of the proinflammatory cytokine TNF-α in the hippocampus. In summary, FUS was required to deliver an effective dose of IVIg to promote hippocampal neurogenesis and modulate the inflammatory milieu.

Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders.

ABC (ATP-binding cassette) transporters represent one of the largest and most diverse superfamily of proteins in living species, playing an important role in many biological processes such as cell homeostasis, cell signaling, drug metabolism and nutrient uptake. Moreover, using the energy generated from ATP hydrolysis, they mediate the efflux of endogenous and exogenous substrates from inside the cells, thereby reducing their intracellular accumulation. At present, 48 ABC transporters have been identified in humans, which were classified into 7 different subfamilies (A to G) according to their phylogenetic analysis. Nevertheless, the most studied members with importance in drug therapeutic efficacy and toxicity include P-glycoprotein (P-gp), a member of the ABCB subfamily, the multidrug-associated proteins (MPRs), members of the ABCC subfamily, and breast cancer resistance protein (BCRP), a member of the ABCG subfamily. They exhibit ubiquitous expression throughout the human body, with a special relevance in barrier tissues like the blood-brain barrier (BBB). At this level, they play a physiological function in tissue protection by reducing or limiting the brain accumulation of neurotoxins. Furthermore, dysfunction of ABC transporters, at expression and/or activity level, has been associated with many neurological diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. Additionally, these transporters are strikingly associated with the pharmacoresistance to central nervous system (CNS) acting drugs, because they contribute to the decrease in drug bioavailability. This article reviews the signaling pathways that regulate the expression and activity of P-gp, BCRP and MRPs subfamilies of transporters, with particular attention at the BBB level, and their mis-regulation in neurological disorders.

Effects of generic exchange of solid oral dosage forms in neurological disorders: a systematic review.

Background Generic drug exchange is common practice in most healthcare systems. While generics certainly contribute to economic savings, the altered drug formulation might be associated with potential therapeutic problems. Given the narrow therapeutic windows in neurologic indications, any detrimental effect on the therapy can lead to significant consequences. Aim of the review This review aims to investigate potential problems related to a switch from brand-name to generic or from generic to generic drug products in patients with neurologic diseases. Method The review was conducted following the PICO framework and the PRISMA guidelines. MEDLINE and Scopus databases were searched for articles published in English and German language between January 1, 1995 and October 17, 2018. Studies included in this review were randomized controlled studies, reviews, systematic reviews, overviews, cohort studies and case-control studies. Studies excluded were letters, comments, authors view, congress or seminar papers and studies with a focus on economic impact or costs. Results were synthesized qualitatively. The primary outcomes were pharmacokinetic parameters such as the area under the curve (AUC), the peak serum concentration (cmax) or the time at which cmax is observed (tmax). Results The search identified 67 studies with a great variety of endpoints and study designs. The leading indication was epilepsy. Two small RCTs were found on lamotrigine switch. Analysis of the other studies found no significant differences in pharmacokinetic parameters when switching to generic drugs. A more heterogeneous picture was revealed regarding hospitalizations, breakthrough seizures, failure of therapy, adherence and patient concerns. Conclusion While most reports were of poor quality, lamotrigine was the drug with the best available data. Summarizing the results of the available studies, pharmacokinetic parameters of antiepileptic drugs show low deviation. In contrast, data on clinical parameters are less consistent. Some studies found increased seizure frequencies and adverse-drug events, while others showed no complications. Adherence and patient satisfaction seemed to be impaired. In daily practice, generic exchange in epilepsy should be a carefully balanced decision, conducted with great caution. Further research is needed, especially regarding neurologic indications other than epilepsy.

Development of an Integrated Tissue Pretreatment Protocol for Enhanced MALDI MS Imaging of Drug Distribution in the Brain.

The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique has attracted intense interest in the visualization of drug distribution in tissues. Its capability to spatially resolve individual molecules makes it a unique tool in drug development and research. However, low drug content and severe ion suppression in tissues hinder its broader application to resolve drug tissue distribution, especially small molecule drugs with a molecular weight below 500 Da. In this work, an integrated tissue pretreatment protocol was developed to enhance the detection of central nervous system drugs in the mouse brain using MALDI MSI. To evaluate the protocol, brain sections from mice dosed intraperitoneally with donepezil, tacrine, clozapine, haloperidol, and aripiprazole were used. The tissue sections were pretreated serially by washing with ammonium acetate solution, incubation with trifluoroacetic acid vapor, and n-hexane washing before MALDI MSI. Compared with the untreated sample, the signal intensities for the test drugs increased by 4.7- to 31.5-fold after pretreatment. Besides the enhancement of signal intensity, fine optimization of pretreatment time and washing solvents preserved the spatial distribution of target drug molecules. The utility of the developed protocol also provided tissue-specific distribution for five drugs which were well resolved when imaged by MALDI MS.

Vital Role of Monoamine Oxidases and Cholinesterases in Central Nervous System Drug Research: A Sharp Dissection of the Pathophysiology.

BACKGROUND: Monoamine oxidase and cholinesterase enzymes are very critical enzymes that regulate the level of neurotransmitters such as acetylcholine and monoamines. Monoamine neurotransmitters and acetylcholine play a very important role in many physiological events. An increase or decrease in the amount of these neurotransmitters is observed in a wide range of central nervous system pathologies. Balancing the amount of these neurotransmitters is important in improving the progression of these diseases. Inhibitors of monoamine oxidase and cholinesterase enzymes are important in symptomatic therapy and delaying progression of a group of central nervous system disease manifested with memory loss, cognitive decline and psychiatric disturbances like depression. OBJECTIVE: In this article, the relationship between central nervous system diseases and the vital role of the enzymes, monoamine oxidase and cholinesterase, is discussed on the pathophysiologic basis, focusing on drug research. CONCLUSION: Monoamine oxidase and cholinesterase enzymes are still a good target for the development of novel drug active substances with optimized pharmacokinetic and pharmacodynamic properties, which can maximize the benefits of current therapy modalities.

Application of separation methods for in vitro prediction of blood-brain barrier permeability-The state of the art.

Despite many efforts, drug discovery pipeline is still a highly inefficient process. Nowadays, when combinatorial chemistry enables to synthesize hundreds of new drugs candidates, methods for rapid assessment of biopharmaceutical parameters of new compounds are highly desired. Over one-third of drugs candidates is rejected because of unsatisfactory pharmacokinetic properties. In the drug discovery process, the blood-brain barrier (BBB) permeability plays a critical role for central nervous system active drugs candidates as well as non-central nervous system active drugs. For this reason, knowledge on the BBB permeability of compounds is essential in the development of new medicines. The review was focused on the application of different separation methods for BBB permeability assessment. Both chromatographic and electrophoretic methods were described. In the article, the advantages and limitations of well-established chromatographic methods like immobilized artificial membrane chromatography or micellar liquid chromatography, and less common techniques were discussed. Special attention was devoted to methods were microemulsion is used as mobile or pseudostationary phases.

Conversion of Benzimidazoles, Imidazothiazoles and Imidazoles into more Potent Central Nervous System Acting Drugs.

BACKGROUND: Benzimidazole (albendazole), imidazothiazole (levamisole) and imidazole (euconazole) are used in chemotherapy of helminthosis and mycosis respectively, with central nervous system (CNS) side effects. But only a limited number of azole groups are used clinically in the treatment of CNS diseases, which are on increase and could not be cured permanently. Due to increased incidence of more challenging new CNS diseases, there is a need for the synthesis of more potent CNS drugs. METHODS: Hence, literature studies were carried out for the identification of common pathways for the synthesis of the three groups of compounds, their CNS properties and the possibility of modifying them to potent CNS drugs. RESULTS: Findings have shown that gloxal with formaldehyde in the presence of ammonia can be converted into imidazole, imidazothiazole and benzimidazole via distillation, condensation, alkylation, acylation, oxidation, cyclization, sulphation and amidation. However, agents such as phosphorus pentoxide, ethanolic potassium hydroxide, sodium hypochlorite, sodium hexafluroaluminate, aniline, calcium acetate, calcium benzoate, sodium hydroxide, aromatic aldehydes, bromoketones, alpha dicarbonyl compounds among others are used as reagents. The furan ring(s) may have a strong capability of penetrating CNS for the treatment of neurological disorders. The products from the three groups have agonistic, antagonistic, mixed agonistic and mixed antagonistic depressant and stimulant activities due to the presence of heteroatoms such as nitrogen, oxygen and sulphur. Imidazole may be the most potent with best characteristics of CNS penetrability and activity followed by imidazothiazole and benzimidazole. CONCLUSION: Azole group is common to all the three classes and may be responsible for some of their CNS effects. The resultant compounds could act via all neurotransmitters, voltage and ligand-gated ion channels and may be chiral.

Role of piperine in CNS diseases: pharmacodynamics, pharmacokinetics and drug interactions.

Introduction: Piperine, the major bioactive component from black pepper, has gained increasing attention for its beneficial effects in the central nervous system (CNS). However, its related pharmacodynamics and brain pharmacokinetics, as well as its interaction with other CNS drugs are lacking, which may hinder its therapeutic and safe use. Areas covered: The current review provides an updated summary on CNS activities of piperine, including anti-epileptic, anti-depressive and neurodegeneration protection effect. The brain pharmacokinetic properties of piperine together with the approaches to enhance its aqueous solubility were summarized. Considering the wide use of black pepper and the well-reported alteration on CYP and transporters by piperine, interactions between piperine and CNS drugs are also illustrated for the first time. Expert opinion: Although the CNS beneficial effects of piperine have been extensively studied in preclinical models, clinical evidence on its CNS application is barely available, which may be attributed to its limited aqueous solubility, unclear pharmacokinetic properties in humans and potential toxicities during long-term use at higher doses. Although beneficial interactions between piperine and certain CNS drugs were often reported in preclinical studies, more mechanistic studies with clinically relevant doses should be conducted to provide guidance on their clinical combination use.

The ANKS1B gene and its associated phenotypes: focus on CNS drug response.

The ANKS1B gene was a top finding in genome-wide association studies (GWAS) of antipsychotic drug response. Subsequent GWAS findings for ANKS1B include cognitive ability, educational attainment, body mass index, response to corticosteroids and drug dependence. We review current human association evidence for ANKS1B, in addition to functional studies that include two published mouse knockouts. The several GWAS findings in humans indicate that phenotypically relevant variation is segregating at the ANKS1B locus. ANKS1B shows strong plausibility for involvement in CNS drug response because it encodes a postsynaptic effector protein that mediates long-term changes to neuronal biology. Forthcoming data from large biobanks should further delineate the role of ANKS1B in CNS drug response.

Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (Mitragyna speciosa): A systematic review.

BACKGROUND AND OBJECTIVE: Kratom (Mitragyna speciosa) is a tropical tree found in southern Thailand and northern states of the Malay Peninsula. Kratom is commercially available and used as an alternative to treat opioid withdrawal. Mitragynine is the major indole alkaloid found in kratom leaves. This review aimed to summarize available pharmacokinetic information about mitragynine. METHODS: PubMed, Scopus, and Web of Science were systematically searched from their inceptions to June 2018. All types of pharmacokinetic studies of mitragynine were included for further systematic review. RESULTS: Seventeen articles were reviewed. Mitragynine is a lipophilic weak base passively transported across the intestinal wall and blood brain barrier. 85-95% is bound to plasma protein and extensively metabolized by phase I and particularly phase II enzymes. Actions on CYP enzymes are unlikely to impact drug metabolism at concentrations likely to exist in kratom-consuming humans. In rats and humans, mitragynine is rapidly absorbed after orally administration (Tmax˜1.5 h, Cmax˜0.3-1.8 µM). Vd was 37-90 L/kg; t1/2 was 3-9 hr; mostly excreted as metabolites in urine. Bioavailability was estimated as 21%. It also rapidly penetrated and redistributed in brain. A quality assessment tool tailored for pharmacokinetic studies was also created which rated some studies of lower value. CONCLUSION: Rudimentary pharmacokinetics of mitragynine was described in this systematic review. However, the discovered studies provided scant information on the role of metabolism and redistribution into tissues nor the rate of excretion.

An experimentally validated approach to calculate the blood-brain barrier permeability of small molecules.

Drug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). Here we develop and experimentally validate a new in silico method to predict quantitatively the BBB permeability for small-molecule drugs. We show accurate prediction of solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations of spontaneous drug diffusion across BBB bilayers. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics. The method is validated computationally against physiological temperature simulations for fast-diffusing compounds, as well as experimentally by direct determination of the compound permeabilities using a transwell assay as an in vitro BBB model. The overall agreement of the predicted values with both direct simulations at physiological temperatures and experimental data is excellent. This new tool has the potential to replace current semi-empirical in silico screening and in vitro permeability measurements in CNS drug discovery.