RESUMO
BACKGROUND AND OBJECTIVES: 7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs. METHODS: Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data. RESULTS: Absorption of 7-HMG was rapid, with a peak plasma concentration (Cmax, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests. CONCLUSIONS: These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.
Assuntos
Mitragyna/química , Modelos Biológicos , Alcaloides de Triptamina e Secologanina/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Cães , Feminino , Meia-Vida , Folhas de Planta , Alcaloides de Triptamina e Secologanina/administração & dosagem , Alcaloides de Triptamina e Secologanina/toxicidade , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Kratom, Mitragyna speciosa Korth., is being widely consumed in the United States for pain management and the reduction of opioid withdrawal symptoms. The central nervous system (CNS) active alkaloids of kratom, including mitragynine, 7-hydroxymitragynine, and numerous additional compounds, are believed to derive their effects through opioid receptor activity. There is no literature describing the systemic exposure of many of these alkaloids after the consumption of kratom. Therefore, we have developed and validated a bioanalytical method for the simultaneous quantitation of 11 kratom alkaloids (mitragynine, 7-hydroxymitragynine, corynantheidine, speciogynine, speciociliatine, paynantheine, corynoxine, corynoxine-B, mitraphylline, ajmalicine, and isospeciofoline) in rat plasma. The validated method was used to analyze oral pharmacokinetic study samples of lyophilized kratom tea (LKT) and a marketed product, OPMS liquid shot, in rats. Among the 11 alkaloids, only mitragynine, 7-hydroxymitragynine, speciociliatine, and corynantheidine showed systemic exposure 8 h postdose, and the dose-normalized systemic exposure of these four alkaloids was higher (1.6-2.4-fold) following the administration of the commercial OPMS liquid. Paynantheine and speciogynine levels were quantifiable up to 1 h postdose, whereas none of the other alkaloids were detected. In summary, the method was successfully applied to quantify the exposure of individual kratom alkaloids after an oral dose of traditional or commercial products. This information will contribute to understanding the role of each alkaloid in the overall pharmacology of kratom and elucidating the pharmacokinetic differences between traditional and commercial kratom products.
Assuntos
Mitragyna/química , Preparações de Plantas/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacocinética , Alcaloides , Animais , Alcaloides Indólicos , Indóis , Masculino , Estrutura Molecular , Oxindóis , Ratos , Ratos Sprague-Dawley , Compostos de EspiroRESUMO
Preparations from the leaves of the kratom plant (Mitragyna speciosa) are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities. Accumulating in vitro evidence has demonstrated select kratom alkaloids, including the abundant indole alkaloid mitragynine, as reversible inhibitors of several cytochromes P450 (CYPs). The objective of this work was to refine the mechanistic understanding of potential kratom-drug interactions by considering both reversible and time-dependent inhibition (TDI) of CYPs in the liver and intestine. Mitragynine was tested against CYP2C9 (diclofenac 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), and CYP3A (midazolam 1'-hydroxylation) activities in human liver microsomes (HLMs) and CYP3A activity in human intestinal microsomes (HIMs). Comparing the absence to presence of NADPH during preincubation of mitragynine with HLMs or HIMs, an â¼7-fold leftward shift in IC50 (â¼20 to 3 µM) toward CYP3A resulted, prompting determination of TDI parameters (HLMs: K I , 4.1 ± 0.9 µM; k inact , 0.068 ± 0.01 min-1; HIMs: K I , 4.2 ± 2.5 µM; k inact , 0.079 ± 0.02 min-1). Mitragynine caused no leftward shift in IC50 toward CYP2C9 (â¼40 µM) and CYP2D6 (â¼1 µM) but was a strong competitive inhibitor of CYP2D6 (K i , 1.17 ± 0.07 µM). Using a recommended mechanistic static model, mitragynine (2-g kratom dose) was predicted to increase dextromethorphan and midazolam area under the plasma concentration-time curve by 1.06- and 5.69-fold, respectively. The predicted midazolam area under the plasma concentration-time curve ratio exceeded the recommended cutoff (1.25), which would have been missed if TDI was not considered. SIGNIFICANCE STATEMENT: Kratom, a botanical natural product increasingly consumed for its opioid-like effects, may precipitate potentially serious pharmacokinetic interactions with drugs. The abundant kratom indole alkaloid mitragynine was shown to be a time-dependent inhibitor of hepatic and intestinal cytochrome P450 3A activity. A mechanistic static model predicted mitragynine to increase systemic exposure to the probe drug substrate midazolam by 5.7-fold, necessitating further evaluation via dynamic models and clinical assessment to advance the understanding of consumer safety associated with kratom use.
Assuntos
Dextrometorfano/farmacocinética , Midazolam/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacocinética , Família 2 do Citocromo P450/antagonistas & inibidores , Interações Medicamentosas , Humanos , Mucosa Intestinal/metabolismo , Microssomos Hepáticos/metabolismoRESUMO
Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.
Assuntos
Mitragyna/química , Plantas Medicinais/química , Alcaloides de Triptamina e Secologanina/química , Animais , Sítios de Ligação , Células HEK293 , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Ensaio Radioligante , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/metabolismo , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Alcaloides de Triptamina e Secologanina/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacologia , Relação Estrutura-AtividadeRESUMO
Mitragyna speciosa, commonly known as Ketum or Biak in Malaysia and Kratom in Thailand, is a native plant to Southeast Asia and has various pharmacological benefits. Mitragynine (MG) is the principal alkaloid found in the leaves of Mitragyna speciosa and has been reported to be responsible for the plant's therapeutic actions. Traditionally, local communities use Kratom preparations for relief from different types of pain. The potential analgesic effects of MG using rodent models have been reported in literatures. We have reviewed the published analgesic and pharmacokinetic studies and all of these findings showed the routes of drug administration, doses employed, and type of vehicles used to solubilize the drug, varied considerably; hence this posted difficulties in predicting the drug's pharmacokinetic-response relationship. A rational approach is warranted for accurate prediction of dose-response relationship; as this is essential for the development of MG as an alternative medicinal drug for pain management. PKPD modeling would serve as a better method to understand the dose-response relationship in future MG preclinical and clinical studies.
Assuntos
Alcaloides/farmacologia , Alcaloides/farmacocinética , Mitragyna/química , Dor/tratamento farmacológico , Alcaloides de Triptamina e Secologanina/farmacologia , Alcaloides de Triptamina e Secologanina/farmacocinética , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Humanos , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologiaRESUMO
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 (TmaxË1.5 h, CmaxË0.3-1.8 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.
Assuntos
Fármacos do Sistema Nervoso Central/farmacocinética , Mitragyna , Alcaloides de Triptamina e Secologanina/farmacocinética , Animais , HumanosRESUMO
1. Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment and as a means of self-treating opioid addiction. 2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine. 3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6, Met8 and Met11) was catalyzed by the CYP3A4. 4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and mono-oxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.
Assuntos
Mitragyna/química , Alcaloides de Triptamina e Secologanina/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa/metabolismo , Humanos , Hidrólise , Metabolômica/métodos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Alcaloides de Triptamina e Secologanina/metabolismo , Espectrometria de Massas em TandemRESUMO
The intestinal permeability of mitragynine was investigated in situ using a single pass intestinal perfusion (SPIP) absorption model, in small intestine of rat using mitragynine in the absence/presence of the permeability markers, P-gp and/or CYP3A4 inhibitors. Mitragynine demonstrated high intestinal permeability (Peff of 1.11 × 10-4 cm/s) that is in the range of highly permeable drugs such as propranolol (Peff of 1.27 × 10-4 cm/s) indicating that it readily crosses the intestine. The addition of azithromycin (P-glycoprotein inhibitor) and ciprofloxacin (CYP3A4 inhibitor) or combination of both has no effect on intestinal permeability of mitragynine across the rat small intestine.
Assuntos
Absorção Intestinal , Alcaloides de Triptamina e Secologanina/farmacocinética , Animais , Azitromicina/farmacologia , Ciprofloxacina/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Masculino , Permeabilidade , Ratos , Ratos Sprague-DawleyRESUMO
Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.
Assuntos
Barreira Hematoencefálica/metabolismo , Alcaloides de Triptamina e Secologanina/farmacocinética , Animais , Transporte Biológico/fisiologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Células Cultivadas , Ciclosporinas/farmacologia , Células Endoteliais/fisiologia , Masculino , Microvasos/fisiologia , Permeabilidade , Ratos Sprague-Dawley , Sus scrofa , SuínosRESUMO
Kratom (Mitragyna speciosa) has been examined for its opioid activity, especially for the treatment of opioid withdrawal and pain. Mitragynine, the most abundant alkaloid in kratom, is thought to be the major psychoactive alkaloid. An HPLC method was developed for the quantification of mitragynine in kratom leaf extracts. In addition, a multiple reaction mode based UPLC-MS/MS method was developed and validated for the quantification of mitragynine in rat plasma. Pharmacokinetic studies were performed by comparing a single intravenous dose of mitragynine (5 mg/kg, mitragynine hydrochloride) to a single oral dose of mitragynine (20 mg/kg, mitragynine hydrochloride), lyophilized kratom tea, and the organic fraction of the lyophilized kratom tea at an equivalent mitragynine dose of 20 mg/kg in rats. After intravenous administration, mitragynine exhibited a biexponential decrease in the concentration-time profile, indicating the fast distribution of mitragynine from the systemic circulation or central compartment to the peripheral compartments. Mitragynine hydrochloride, lyophilized kratom tea, and the lyophilized kratom tea organic fraction were dosed orally and the absolute oral bioavailability of mitragynine in rats was found to be 1.5- and 1.8-fold higher than that of mitragynine dosed alone. The results provide evidence that an equivalent oral dose of the traditional preparation (lyophilized kratom tea) and formulated/manufactured products (organic fraction) of kratom leaves provide better systemic exposure of mitragynine than that of mitragynine dosed alone.
Assuntos
Mitragyna/química , Extratos Vegetais/farmacocinética , Folhas de Planta/química , Alcaloides de Triptamina e Secologanina/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Trânsito Gastrointestinal , Injeções Intravenosas , Masculino , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Alcaloides de Triptamina e Secologanina/administração & dosagem , Alcaloides de Triptamina e Secologanina/sangue , Alcaloides de Triptamina e Secologanina/isolamento & purificaçãoRESUMO
BACKGROUND: Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. METHODS: Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. RESULTS: Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. CONCLUSION: This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic linearity and parameters reported are necessary pharmacological information of Kratom, and there is a possibility for it to be developed medically as a pain killer or better opioid substitute in the future.
Assuntos
Analgésicos/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacocinética , Adulto , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Mitragyna/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Estudos Prospectivos , Transtornos Relacionados ao Uso de Substâncias/sangue , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field.
Assuntos
Antipsicóticos/farmacologia , Apocynaceae/química , Receptores de Dopamina D2/metabolismo , Alcaloides de Triptamina e Secologanina/farmacologia , Sinaptossomos/efeitos dos fármacos , Animais , Antipsicóticos/farmacocinética , Autorradiografia , Dopamina/metabolismo , Frutas/química , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Putamen/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina/farmacocinéticaRESUMO
Mitragyna speciosa (kratom) is a popular herb in Southeast Asia, which is traditionally used to treat withdrawal symptoms associated with opiate addiction. Mitragynine, 7-hydroxymitragynine, and mitraphylline are reported to be the central nervous system active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark of Uncaria tomentosa (cat's claw). Several therapeutic properties have been reported for these compounds but limited information is available on the absorption and distribution properties. This study focuses on evaluating the absorption, distribution, metabolism, and excretion (ADME) properties of these compounds and their effect on major efflux transporter P-glycoprotein, using in vitro methods. Quantitative analysis was performed by the Q-TOF LC-MS system. Mitragynine was unstable in simulated gastric fluid with 26â% degradation but stable in simulated intestinal fluid. 7-Hydroxymitragynine degraded up to 27â% in simulated gastric fluid, which could account for its conversion to mitragynine (23â%), while only 6â% degradation was seen in simulated intestinal fluid. Mitraphylline was stable in simulated gastric fluid but unstable in simulated intestinal fluid (13.6â% degradation). Mitragynine and 7-hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCK monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers. Mitragynine was found to be metabolically stable in both human liver microsomes and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by human liver microsomes with half-lives of 24 and 50 min, respectively. All three compounds exhibited high plasma protein binding (> 90â%) determined by equilibrium dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-glycoprotein with EC50 values of 18.2 ± 3.6 µM and 32.4 ± 1.9 µM, respectively, determined by the calcein-AM fluorescent assay, while no inhibition was seen with mitraphylline. These data indicate the possibility of a drug interaction if mitragynine and 7-hydroxymitragynine are coadministered with drugs that are P-glycoprotein substrates.
Assuntos
Alcaloides Indólicos/farmacocinética , Mitragyna/química , Extratos Vegetais/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacocinética , Uncaria/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Transporte Biológico , Células CACO-2 , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Medicina Tradicional do Leste Asiático , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxindóis , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Plantas Medicinais , Receptores Opioides/metabolismo , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/metabolismoRESUMO
A simple, sensitive and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine the concentrations of 7-hydroxymitragynine in rat plasma. Following a single-step liquid-liquid extraction of plasma samples using chloroform, 7-hydroxymitragynine and the internal standard (tryptoline) were separated on an Acquity UPLC(TM) BEH C18 (1.7 µm, 2.1 × 50 mm) column using an isocratic elution at a flow rate of 0.2 mL/min. The mobile phase consisted of 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile (10:90, v/v). The run time was 2.5 min. The analysis was carried out under the multiple reaction-monitoring mode using positive electrospray ionization. Protonated ions [M + H](+) and their respective product ions were monitored at the following transitions: 415 â 190 for 7-hydroxymitragynine and 173 â 144 for the internal standard. The calibration curve was linear over the range of 10-4000 ng/mL (r(2) = 0.999) with a lower limit of quantification of 10 ng/mL. The extraction recoveries ranged from 62.0 to 67.3% at concentrations of 20, 600 and 3200 ng/mL). Intra- and inter-day assay precisions (relative standard deviation) were <15% and the accuracy was within 96.5-104.0%. This validated method was successfully applied to quantify 7-hydroxymitragynine in rat plasma following intravenous administration.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Alcaloides de Triptamina e Secologanina/sangue , Espectrometria de Massas em Tandem/métodos , Analgésicos Opioides/agonistas , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacocinética , Sensibilidade e EspecificidadeRESUMO
Mitragyna speciosa (Kratom in Thai), native in Southeast Asia, is increasingly misused as a herbal drug of abuse. During metabolism studies on the Kratom alkaloids mitragynine, its diastereomers speciogynine and speciociliatine as well as paynantheine in rats and humans, further isomeric compounds were detected in Kratom users' urine. The question arose whether these compounds were formed from the low abundant, isomeric alkaloids mitraciliatine (MC) and isopaynantheine (ISO-PAY). Therefore, the aim of the presented study was to identify using liquid chromatography-linear ion trap-mass spectrometry their phase I and II metabolites in rat urine after administration of pure MC or ISO-PAY, to confirm their formation in humans, and finally to confirm whether the above-mentioned isomeric compounds in human urine represent MC and ISO-PAY and/or their metabolites. The metabolic pathways of both alkaloids in rats were found to be comparable to those of their corresponding diastereomers. In the human urines tested, not all metabolites found in rats could be detected because of the much lower amounts of MC and ISO-PAY in Kratom. However, all the above-mentioned so far unknown isomeric compounds could be identified in the human urine samples as MC, ISO-PAY and/or their metabolites. The used LC separation was also suitable for the differentiation of all other Kratom alkaloids and their metabolites in human urine.
Assuntos
Cromatografia Líquida/métodos , Alcaloides Indólicos/farmacocinética , Espectrometria de Massas/métodos , Mitragyna/química , Alcaloides de Triptamina e Secologanina/farmacocinética , Animais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/urina , Masculino , Redes e Vias Metabólicas , Folhas de Planta/química , Ratos , Ratos Wistar , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/urina , EstereoisomerismoRESUMO
A new solid phase extraction method for rapid high performance liquid chromatography-UV determination of mitragynine in plasma has been developed. Optimal separation was achieved with an isocratic mobile phase consisting of acetonitrile-ammonium acetate buffer, 50 mM at pH 5.0 (50:50, v/v). The method had limits of detection and quantification of 0.025 and 0.050 microg/mL, respectively. The method was accurate and precise for the quantitative analysis of mitragynine in human and rat plasma with within-day and between-day accuracies between 84.0 and 109.6%, and their precision values were between 1.7 and 16.8%. Additional advantages over known methods are related to the solid phase extraction technique for sample preparation which yields a clean chromatogram, a short total analysis time, requires a smaller amount of plasma samples and has good assay sensitivity for bioanalytical application. The method was successfully applied in pharmacokinetic and stability studies of mitragynine. In the present study, mitragynine was found to be fairly stable during storage and sample preparation. The present study showed for the first time the detailed pharmacokinetic profiles of mitragynine. Following intravenous administration, mitragynine demonstrated a biphasic elimination from plasma. Oral absorption of the drug was slow, prolonged and was incomplete, with a calculated absolute oral bioavailability value of 3.03%. The variations observed in previous pharmacokinetic studies after oral administration of mitragynine could be attributed to its poor bioavailability rather than to the differences in assay method, metabolic saturation or mitragynine dose.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/sangue , Alcaloides de Triptamina e Secologanina/sangue , Extração em Fase Sólida/métodos , Espectrofotometria Ultravioleta/métodos , Animais , Humanos , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Ratos , Ratos Sprague-Dawley , Alcaloides de Triptamina e Secologanina/administração & dosagem , Alcaloides de Triptamina e Secologanina/farmacocinéticaRESUMO
This study used for the first time LC-MS/MS for the analysis of mitragynine (MIT), a mu-opioid agonist with antinociceptive and antitussive properties, in rat plasma. Mitragynine and the internal standard (amitriptyline) were extracted from plasma with hexane-isoamyl alcohol and resolved on a Lichrospher RP-SelectB column (9.80 and 12.90 min, respectively). The quantification limit was 0.2 ng/mL within a linear range of 0.2-1000 ng/mL. The method was applied to quantify mitragynine in plasma samples of rats (n=8 per sampling time) treated with a single oral dose of 20 mg/kg. The following pharmacokinetic parameters were obtained (mean): maximum plasma concentration: 424 ng/mL; time to reach maximum plasma concentration: 1.26 h; elimination half-life: 3.85 h, apparent total clearance: 6.35 L/h/kg, and apparent volume of distribution: 37.90 L/kg.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Alcaloides de Triptamina e Secologanina/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Masculino , Ratos , Ratos Wistar , Alcaloides de Triptamina e Secologanina/farmacocinéticaRESUMO
A simple HPLC technique for determining mitragynine levels in serum was developed. The separation system consisted of a C18 column heated to 35 degrees C, a methanol-water (80:20, v/v) mobile phase, a flow rate of 0.8 mL/min and detection in the ultraviolet at 225 nm. Mitragynine, with a retention time of 10.09 min, was well resolved from any interferences in human serum and the internal standard peak. The calibration curve was linear from 0.1 to 10 microg/mL (r = 0.9995). Extraction of mitragy-nine from alkalinized serum using diethyl ether gave a high recovery (>or=85%). The intra- and inter-day precisions of the method were 4.29-5.88%RSD and 7.06-8.45%RSD, respectively. The accuracy ranged from -9.54 to +0.67%DEV. The limit of detection was 0.03 microg/mL and the lower limit of quantification was 0.1 microg/mL. Mitragynine in the stock solution was stable during 30 days of storage at 4 degrees C. This method was successfully applied to determine the pharmacokinetic characteristics of mitragynine levels in the serum of rats after it was administered orally.