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1.
Eur J Drug Metab Pharmacokinet ; 41(6): 689-703, 2016 Dec.
Article in English | MEDLINE | ID: mdl-26254911

ABSTRACT

BACKGROUND AND OBJECTIVE: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug's therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. METHODS: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. RESULTS: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug-metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. CONCLUSION: The developed PBPK model can be regarded as the first step towards a PBPK-pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.


Subject(s)
Amiodarone/analogs & derivatives , Amiodarone/pharmacokinetics , Anti-Arrhythmia Agents/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Models, Biological , Potassium Channel Blockers/pharmacokinetics , Algorithms , Amiodarone/administration & dosage , Amiodarone/adverse effects , Amiodarone/blood , Amiodarone/metabolism , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/adverse effects , Anti-Arrhythmia Agents/metabolism , Biotransformation , Blood-Brain Barrier/metabolism , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/adverse effects , Cytochrome P-450 Enzyme Inhibitors/metabolism , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/metabolism , Half-Life , Infusions, Intravenous , Injections, Intravenous , Male , Metabolic Clearance Rate , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Potassium Channel Blockers/administration & dosage , Potassium Channel Blockers/adverse effects , Potassium Channel Blockers/metabolism , Rats , Tissue Distribution
2.
Curr Drug Metab ; 16(9): 807-15, 2015.
Article in English | MEDLINE | ID: mdl-26264197

ABSTRACT

In the past decade, mass spectrometry imaging (MSI) has received an increasing amount of attention due to its ability in displaying the spatial distribution of a wide range of molecules, including peptides, proteins, lipids, endogenous and exogenous metabolites, and xenobiotics in biological tissues. Information regarding drug localization within tissues provides a better understanding of pharmacokinetic behaviors and pharmacological and toxicological effects. This review presents an introduction to MSI, along with an in-depth analysis of its general process. In addition, we highlighted several examples of various intensive applications of imaging drugs and metabolites in tissues by mass spectrometry. Furthermore, we present the prospect of quantitative MSI of small molecular chemicals, which may be particularly attractive to researchers in the pharmaceutical industry today. It is expected that with technological advancement, MSI will become an increasingly powerful tool in drug disposition studies and other fields of biomedical research.


Subject(s)
Mass Spectrometry/methods , Pharmaceutical Preparations/analysis , Xenobiotics/analysis , Animals , Humans , Pharmaceutical Preparations/metabolism , Technology, Pharmaceutical/methods , Tissue Distribution , Xenobiotics/pharmacokinetics
3.
J Pharm Biomed Anal ; 97: 166-77, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24879483

ABSTRACT

Alpinia oxyphylla (Yizhi) capsularfruits are commonly used in traditional medicine. Pharmacological studies have demonstrated that A. oxyphylla capsularfruits have some beneficial roles. Besides volatile oil, sesquiterpenes, diarylheptanoids and flavonoids are main bioactive constituents occurring in the Yizhi capsularfruits. The representative constituents include tectochrysin, izalpinin, chrysin, apigenin-4',7-dimethylether, kaempferide, yakuchinone A, yakuchinone B, oxyphyllacinol and nootkatone. Their content levels in the fruit and its pharmaceutical preparations have been reported by our group. The nine phytochemicals are also the major components present in the Yizhi alcoholic extracts, which have anti-diarrheal activities. However, the fates of these constituents in the body after oral or intravenous administration remain largely unknown. In the present study, we focus on these phytochemicals albeit other concomitant compounds. The chemicals and their metabolites in rat plasma were identified using liquid chromatography/tandem mass spectrometry with selected reaction monitoring mode after orally administered Yizhi extract to rats. Rat plasma samples were treated by methanol precipitation, acidic or enzymatic hydrolysis. This target analysis study revealed that: (1) low or trace plasma levels of parent chemicals were measured after p.o. administration of Yizhi extract, Suoquan capsules and pills to rats; (2) flavonoids and diarylheptanoids formed mainly monoglucuronide metabolites; however, diglucuronide metabolites for chrysin, izalpinin and kaempferide were also detected; (3) metabolic reduction of Yizhi diarylheptanoids occurred in rats. Yakuchinone B was reduced to yakuchinone A and then to oxyphyllacinol in a stepwise manner and subsequently glucuronidated by UDP-glucuronosyl transferase. Further research is needed to characterize the UDP-glucuronosyl transferase and reductase involved in the biotransformation of Yizhi chemicals.


Subject(s)
Phytochemicals/blood , Phytochemicals/metabolism , Plant Extracts/blood , Plant Extracts/chemistry , Administration, Oral , Alpinia , Animals , Biotransformation , Chromatography, Liquid/methods , Male , Phytochemicals/chemistry , Plant Extracts/administration & dosage , Plant Extracts/metabolism , Rats , Tandem Mass Spectrometry/methods
4.
Molecules ; 19(4): 4510-23, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24727421

ABSTRACT

Plant secondary metabolites are known to not only play a key role in the adaptation of plants to their environment, but also represent an important source of active pharmaceuticals. Alpinia oxyphylla capsular fruits, made up of seeds and pericarps, are commonly used in traditional East Asian medicines. In clinical utilization of these capsular fruits, inconsistent processing approaches (i.e., hulling pericarps or not) are employed, with the potential of leading to differential pharmacological effects. Therefore, an important question arises whether the content levels of pharmacologically active chemicals between the seeds and pericarps of A. oxyphylla are comparable. Nine secondary metabolites present in A. oxyphylla capsular fruits, including flavonoids (e.g., tectochrysin, izalpinin, chrysin, apigenin-4',7-dimethylether and kaempferide), diarylheptanoids (e.g., yakuchinone A and B and oxyphyllacinol) and sesquiterpenes (e.g., nootkatone), were regarded as representative constituents with putative pharmacological activities. This work aimed to investigate the abundance of the nine constituents in the seeds and pericarps of A. oxyphylla. Thirteen batches of A. oxyphylla capsular fruits were gathered from different production regions. Accordingly, an ultra-fast high performance liquid chromatography/quadrupole tandem mass spectrometry (UFLC-MS/MS) method was developed and validated. We found that: (1) the nine secondary metabolites were differentially concentrated in seeds and fruit capsules; (2) nootkatone is predominantly distributed in the seeds; in contrast, the flavonoids and diarylheptanoids are mainly deposited in the capsules; and (3) the content levels of the nine secondary metabolites occurring in the capsules varied greatly among different production regions, although the nootkatone levels in the seeds were comparable among production regions. These results are helpful to evaluating and elucidating pharmacological activities of A. oxyphylla capsular fruits. Additionally, it may be of interest to elucidate the mechanisms involved in the distinct accumulation profiles of these secondary metabolites between seeds and pericarps.


Subject(s)
Alpinia/chemistry , Flavonoids/classification , Plant Extracts/analysis , Seeds/chemistry , Sesquiterpenes/classification , China , Chromatography, High Pressure Liquid/methods , Climate , Flavonoids/isolation & purification , Geography , Organ Specificity , Sesquiterpenes/isolation & purification , Tandem Mass Spectrometry
5.
Curr Drug Metab ; 15(8): 767-90, 2014.
Article in English | MEDLINE | ID: mdl-25705906

ABSTRACT

Pharmacokinetic (PK) drug-drug interactions (DDIs) give rise to adverse events and/or reduced efficacy. Comprehensive, systematic and mechanistic approaches have been applied in the evaluation, propagation and management of the interaction potential of a new drug during its development and clinical use. However, the role of drug metabolite(s) in DDIs was not extensively investigated. Recently, regulatory bodies have proposed that metabolites at ≥25% of the parent drug's area under the time-concentration curve (AUC) and/or >10% of the total drug-related exposure should be investigated in vitro for DDI potential. This review aimed to identify the drugs and their metabolites meeting the official guidance's criteria for DDI studies, and to assess whether the eligible drugs caused significant clinical PK DDIs and furthermore whether the metabolites contributed to the observed PK DDIs. Eighty seven drugs were eligible and nearly 45% (39/87) drugs were not reported with clinical PK DDIs. About 78% (68/87) drugs demonstrated inhibitory and/or inducible effects on drug-metabolizing enzymes and/or drug transporters; while the remaining 19 (22%) parent drugs showed no such effects. For 8 drugs (~9%), their metabolites were able to inhibit and/or induce the drug-metabolizing enzymes and drug transporters. Three drugmetabolite pairs were found to be the perpetrators of the complex PK DDIs. Our retrospective analysis suggested that the PK DDI risks caused by metabolites alone might not be high, which is somewhat different from the conclusions from some other studies on this topic. However, circulating drugs often work as perpetrators of PK DDIs suggesting a need for more efforts to characterize the roles of their metabolites. Our study should be of value in stimulating discussions among the scientific community on this important topic.


Subject(s)
Drug Interactions , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Area Under Curve , Enzymes/metabolism , Humans , Membrane Transport Proteins/metabolism
6.
Curr Drug Metab ; 15(8): 761-6, 2014.
Article in English | MEDLINE | ID: mdl-25705907

ABSTRACT

Drug-drug interaction (DDI) is one important topic in drug discovery, drug development and clinical practice. Recently, a novel approach, in vivo information-guided prediction (IVIP), was introduced for predicting the magnitude of pharmacokinetic DDIs which are caused by changes in cytochrome P450 (CYP) activity. This approach utilizes two parameters, i.e. CR (the apparent contribution of the target metabolizing enzyme to the clearance of the substrate drug) and IX (the apparent effect of a perpetrator on the target CYP) to describe the magnitude of DDI between a perpetrator and a victim drug. The essential concept of this method assumes that at a given dose level, the IX for a given perpetrator remains constant whatever the victim drug is. Usually, this IVIP method is only based on information from clinical studies and does not need in vitro information. In this review, basic concept, application and extension, as well as pros and cons of the IVIP method were presented. How to apply this approach was also discussed. Thus far, this method displayed good performance in predicting DDIs associated with CYPs, and can be used to forecast the magnitude of a large number of possible DDIs, of which only a small portion have been investigated in clinical studies. The key concept of this static approach could even be implemented in dynamic modeling to assess risks of DDIs involving drug transporters.


Subject(s)
Drug Interactions , Models, Biological , Pharmacokinetics , Computer Simulation , Dose-Response Relationship, Drug , Drug Design , Humans , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/metabolism
7.
Eur J Cancer ; 46(10): 1856-65, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20335017

ABSTRACT

Life-threatening diarrhoea is observed in up to 25% of cancer patients receiving irinotecan. The associations between the UGT1A1*28 polymorphism and irinotecan-induced diarrhoea remains controversial because of conflicting data in the literature. Meta-analyses were performed on published data in terms of relationships between UGT1A1*28 and severe diarrhoea. We searched databases for relevant studies that were published in English or Chinese. Two reviewers extracted data and assessed methodological quality. UGT1A1*28 related odds ratios (ORs) were pooled by use of a fixed-effects model. The studies included were stratified into subgroups representing different races and irinotecan doses, and meta-regression analyses were performed to investigate the effect of study characteristics on the association between UGT1A1*28 and diarrhoea. Twenty trials including a total of 1760 cancer patients were included. The risk of severe diarrhoea at medium and high irinotecan doses was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 genotype (OR=3.69, 95% confidence interval [CI]=2.00-6.83; P<0.001). Considering the patients with a UGT1A1*1/*28 genotype, the risk of toxicity was also higher than among those with a wild-type genotype at medium and high doses (OR=1.92, 95% CI=1.31-2.82; P=0.001). No association was observed between UGT1A1*28 and severe diarrhoea at low doses (<125 mg/m(2)). In conclusion, patients carrying UGT1A1*28 allele(s) are at an increased risk of irinotecan-induced severe diarrhoea. This increased risk is only apparent in those who are administrated with medium or high irinotecan doses.


Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/analogs & derivatives , Diarrhea/chemically induced , Glucuronosyltransferase/genetics , Neoplasms/drug therapy , Polymorphism, Genetic/genetics , Aged , Camptothecin/adverse effects , Clinical Trials as Topic , Diarrhea/genetics , Female , Humans , Irinotecan , Male , Middle Aged , Neoplasms/genetics
8.
Drug Metab Dispos ; 38(5): 817-23, 2010 May.
Article in English | MEDLINE | ID: mdl-20164111

ABSTRACT

Controversy exists concerning the sex-dependent differences in cytochrome P450 3A activity in humans. Meta-analysis of selected studies may address this question. Meta-analysis was performed on published or unpublished data in terms of sex-dependent differences in midazolam (MDZ) disposition in humans. The following pharmacokinetic parameters were included for the analysis: MDZ oral and systemic clearance, area under the concentration-time curve (AUC) of oral and intravenous MDZ, MDZ oral bioavailability (F), and MDZ gastrointestinal extraction (E(G)). Ten studies including 409 healthy volunteers were identified. Women exhibited 16% higher weight-corrected MDZ oral clearance (P < 0.001) and 20% higher systemic clearance (P = 0.002) than men. No significant difference in the AUC after oral dosing of MDZ was noted between sexes. Women showed lower AUC of intravenous MDZ than men (P = 0.02). No sex-dependent differences were observed in F and E(G). In conclusion, women showed significantly greater hepatic CYP3A activity than men, whereas no sex-dependent difference in intestinal CYP3A activity was observed.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Midazolam/metabolism , Midazolam/pharmacokinetics , Sex Characteristics , Administration, Oral , Area Under Curve , Biological Availability , Cytochrome P-450 CYP3A/genetics , Female , Humans , Injections, Intravenous , Intestinal Absorption/physiology , Male , Metabolic Clearance Rate/physiology , Midazolam/administration & dosage , Midazolam/analogs & derivatives , Midazolam/blood
10.
Clin Chim Acta ; 408(1-2): 92-7, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19654004

ABSTRACT

BACKGROUND: We determined if endogenous cortisol 6 beta-hydroxylation clearance [CL(m(6 beta))] could be used as a reliable index for in vivo CYP3A phenotyping (including both hepatic and intestinal CYP3A activities). METHODS: In this study, 16 healthy volunteers received a single 7.5 mg oral dose of midazolam (MDZ). Blood samples were drawn up to 24 h after dosing. Urine samples were collected at various time periods after dosing. MDZ, 1-hydroxymidazolam (1-OHMDZ), cortisol (F) and 6 beta-hydroxycortisol (6 beta-OHF) in plasma or urine were determined by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV). RESULTS: CL(m(6 beta)) was poorly correlated (P>0.2) with MDZ oral clearance [CL(oral(MDZ))] and the ratio of AUC(0-infinity(1-OHMDZ)) versus AUC(0-infinity(MDZ)) [MR((AUC))]. However, when examining the data obtained from male volunteers exclusively, strong correlations were observed between CL(m(6 beta)) and CL(oral(MDZ)). Larger interindividual and intraindividual variabilities were observed in urinary ratio of 6 beta-OHF/F compared with CL(m(6 beta)). CONCLUSION: CL(m(6 beta)) cannot reflect the overall CYP3A activity accurately and quantitatively in the population.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Hydrocortisone/metabolism , Phenotype , Administration, Oral , Cytochrome P-450 CYP3A/genetics , Female , Humans , Hydrocortisone/analogs & derivatives , Hydrocortisone/blood , Hydrocortisone/urine , Hydroxylation , Male , Midazolam/administration & dosage , Midazolam/analogs & derivatives , Midazolam/blood , Midazolam/pharmacokinetics , Midazolam/urine , Time Factors
11.
Chinese Journal of Burns ; (6): 42-45, 2006.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-312509

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the biological characteristics of dermal fibroblasts of the diabetic rats with deep partial thickness scald, and to explore its relationship with delayed wound healing due to diabetes.</p><p><b>METHODS</b>Sprague-Dawley rats weighing 250 g were randomly divided into control (NM, n=40) and STZ-induced diabetic (DM, n=50) groups, and then deep partial thickness scald involving 10% TBSA were reproduced in the two groups. Skin samples were harvested from the wounds on 0, 3, 7, 14 and 21 post scald day (PSD) for the determination of certain histological characteristics.</p><p><b>RESULTS</b>The thickness of dermis layer in DM group before injury was obviously thinner than that in NM group (P < 0.01). There was an infiltration of a large amount of chronic inflammatory cells and increased content of cutaneous glucose in the dermal tissue in DM group (2.77 mg/g) compared with 0.85 mg/g in NM group, (P < 0.01). An accumulation of advanced glycation end products (AGEs) was found in the dermal tissue in DM group. After the scalding, the percentage of fibroblasts in S phase and hydroxyproline synthesis in DM group was evidently lower than those in NM group. But the apoptosis rate of fibroblasts was much higher in DM group than that in NM group (P < 0.05 or 0.01).</p><p><b>CONCLUSION</b>It is found that the high contents of glucose and AGEs in diabetic skin exert untoward effects on biological characteristics of dermal fibroblast, probably constituting one of the underlying mechanisms of delay wound healing of scald in diabetic rats.</p>


Subject(s)
Animals , Male , Rats , Burns , Metabolism , Pathology , Diabetes Mellitus, Experimental , Fibroblasts , Cell Biology , Glycation End Products, Advanced , Metabolism , Rats, Sprague-Dawley , Skin , Metabolism , Pathology , Wound Healing
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