Suramus Biopharm

Bangalore, India

Suramus Biopharm

Bangalore, India
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Mullangi R.,Jubilant Biosys | Srinivas N.R.,Suramus Biopharm
Biomedical Chromatography | Year: 2013

Clinical investigations of choleteryl ester transfer protein (CETP) inhibitors are still underway owing to its promise of reducing risk factors in patients with cardiovascular disease. Although several CETP inhibitors have reached late phase clinical testing, there is a paucity of publications that describe the determination of various CETP inhibitors in human and/or animal matrices. An attempt is made in this review to collate bioanalytical information on three CETP inhibitors (anacetrapib, dalcetrapib and torcetrapib) and its metabolites, where data were available and reported. As elaborated in the review, owing to numerous structural issues coupled with chromatography/detection challenges indigenous to the class, a wide array of analytical tools, detection systems, interesting process manipulations and separation nuances have been utilized for the quantitative analysis of CETP inhibitors and applicable metabolites. Copyright © 2013 John Wiley & Sons, Ltd. © 2013 John Wiley & Sons, Ltd.


D'Souza H.J.B.,Lotus Labs. Pvt. Ltd. | Pai B.,Lotus Labs. Pvt. Ltd. | Kumar A.,Lotus Labs. Pvt. Ltd. | Shekar R.,Lotus Labs. Pvt. Ltd. | And 2 more authors.
Biomedical Chromatography | Year: 2010

While the practice of using a smaller number of non-zero standards (typically seven to eight) has not been entertained in routine bioanalytical work, it is important to innovate and be pragmatic about minimizing the number of calibration standards to promote cost-eff ective and speedy assessment. In this exercise, two important compounds, omeprazole and clopidogrel carboxylic acid, were considered. Additionally, both analytes off ered a 1000-fold calibration curve range with eight non-zero standards to permit a systematic evaluation. Accordingly various scenarios of post-hoc analysis of the calibration data were formulated which included step-wise reduction of the number of calibration standards from a maximum of n = 8 to a minimum of n = 3. In all the scenarios evaluated in this exercise, a calibration curve was reconstructed and both quality control samples and in vivo pharmacokinetics were calculated in each instance. Based on the data generated in this exercise, a minimum of three non-zero calibration standards were adequate to predict the quality control samples with the predefined accuracy and precision estimates for both omeprazole and clopidogrel carboxylic acid. Additionally, the in vivo pharmacokinetic characterization of the chosen compounds was not hampered by the reduction of calibration standards (from n = 8 to n = 3). Hence, consideration for reducing number of calibration standards in bioanalytical work may provide a viable alternative in several situations such as formulation screening strategies, routine therapeutic drug monitoring and sparse sample analyses. Copyright © 2009 John Wiley & Sons, Ltd.


Manjunath S.J.,Lotus Labs Pvt. Ltd | Kamath N.,Lotus Labs Pvt. Ltd | Shekar A.K.R.,Lotus Labs Pvt. Ltd | Srinivas N.R.,Suramus Biopharm | Kristjansson F.,Lotus Labs Pvt. Ltd
Biomedical Chromatography | Year: 2010

Sensitivity enhancement via summation of multiple MRM transition pairs is gaining popularity in tandem mass spectrometric assays. Numerous validation experiments describing the assays for two model substrates, clopidogrel and ramiprilat, were performed. The quantitation of clopidogrel was achieved by the summation of transition pairs m/z 322.2 to m/z 212.0 and m/z 322.2 to m/z 184.0, while that of ramiprilat was achieved by the summation of transition pairs m/z 389.2 to m/z 206.1 and m/z 389.2 to m/z156.1. The use of summation approach achieved sensitivities of >2 fold for both compounds as compared with the reported single MRM transition pair assays. The validation experiments addressed some important assay development issues, such as: (a) lack of impact of matrix effect; (b) unequivocal verification of the percentage contribution of each MRM transition pair towards sensitivity; (c) sensitivity enhancement factor achieved by summation approach of MRM transition pairs; and (d) accurate prediction of quality control samples using summation approach vs a single MRM transition pair. In summary, the appropriateness of using two MRM transition pairs for quantitation was demonstrated for both clopidogrel and ramiprilat. Additionally, pharmacokinetic application of the MRM transition pair assays using a summation approach was established for the two compounds. Copyright © 2009 John Wiley & Sons, Ltd.


Srinivas N.R.,Suramus Biopharm
Journal of Pharmacy and Pharmaceutical Sciences | Year: 2013

Cranberry juice is a popular beverage with many health benefits. It has anthocyanins to supplement dietary needs. Based on in vitro evidence cranberry juice is an inhibitor of CYP enzymes and at higher amounts as potent as ketoconazole (CYP3A) and fluconazole (CYP2C9). There is, however, a discrepancy between in vitro and in vivo observations with respect to a number of substrates (cyclosporine, warfarin, flurbiprofen, tizanidine, diclofenac, amoxicillin, ceflacor); with the exception of a single report on midazolam, where there was a moderate increase in the AUC of midazolam in subjects pre-treated with cranberry juice. However, another study questions the clinical relevancy of in vivo pharmacokinetic interaction between cranberry juice and midazolam. The controversy may be due to a) under in vitro conditions all anthocyanin principles may be available to have a concerted effort in CYP inhibition; however, limited anthocyanin principles may be bioavailable with varying low levels in the in vivo studies; b) a faster clearance of the active anthocyanin principles under in vivo conditions may occur, leading to low threshold levels for CYP inhibition; c) efficient protein binding and/or rapid tissue uptake of the substrate may have precluded the drug availability to the enzymes in the in vivo studies. With respect to pharmacodynamic aspects, while the debate continues on the issue of an interaction between warfarin and cranberry juice, the summation of the pharmacodynamics data obtained in patients and healthy subjects from different prospectively designed and controlled clinical trials does not provide overwhelming support for the existence of a pharmacodynamic drug interaction for normal cranberry juice ingestion. However, it is apparent that consumption of large quantities of cranberry juice (about 1-2 L per day) or cranberry juice concentrates in supplements for an extended time period (>3-4 weeks) may temporally alter the effect of warfarin. Therefore, the total avoidance of cranberry juice by warfarin users may not be warranted by the published studies. However, in certain situations of higher intake of cranberry juice or concentrate there may be a need to monitor both warfarin doses and its effect.


Srinivas N.R.,Suramus Biopharm
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2013

The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies. © 2013 Springer-Verlag France.


Baicalin was extensively researched for utility in a number of therapeutic areas owing to its anti-inflammatory, anti-oxidant, anti-bacterial, and anti-cancer properties. A number of preclinical studies, in vitro work, and mechanistic studies were performed to understand the absorption, distribution, metabolism, and excretion profiles of baicalin. The absorption of baicalin involved several complexities: the restriction to two distant sites; the conversion of baicalin to baicalein; the possible role of transporter(s); and enhanced absorption due to breakdown of conjugates by beta-glucuronidase. Limited distribution data suggest that baicalin reached several sites such as the brain, eye lens, thymus, etc. Hepatobiliary recycling also served as a distribution phase for sustained delivery of baicalin. Metabolism data suggest the rapid conversion of baicalin to baicalein, which was extensively subjected to Phase 2 metabolism, conjugates baicalein glucuronide/sulfate have been identified. Limited excretion data suggest involvement of renal and faecal routesglucuronide and sulfate conjugates were excreted in urine and faeces (via biliary excretion). The published data on baicalin suggest imminent challenges for developing baicalin and/or during co-administration with other agents. These challenges are absorption related (transporter or changes in the microenvironment), metabolism related (CYP2B6 induction and/or CYP2E1 inhibition), and excretion/efflux related (competitive biliary pathway and/or OATP1B1 transport).


Srinivas N.R.,Suramus Biopharm
Journal of Pain and Palliative Care Pharmacotherapy | Year: 2013

In spite of numerous investigations and decades of research, there is still a void in the complete understanding of the therapeutic action of morphine due to the complex nature of its pharmacokinetic/metabolic disposition coupled with elusive pharmacodynamics. This commentary attempts to collate current information on this very important topic and provide perspective to further tease out the relationship between morphine and its metabolites to its purported clinical effect. Similar to numerous acute therapies that need a close vigil for therapy optimization, postoperative pain management with morphine is a challenge due to its extreme intrasubject variability, a fragile therapeutic index, and complex pharmacology interlinked with formation and transport of active metabolite(s). Although numerous investigations of pharmacokinetics and pharmacodynamic effects of morphine and its active glucuronide metabolites have been carried out and excellent data published, still there remains a void in complete understanding of desired therapeutic levels for a meaningful therapeutic outcome without the avoidance of morphine-related side effect profile. The 2009 report of Hammoud et al. (Pain. 2009;144:139-146) confirms the challenges of which one need to be aware during postoperative pain management with morphine in spite of well-controlled intravenous titration using an institutional protocol. These authors have attempted to correlate the plasma concentrations of morphine and its key metabolites, morphine-3-glucuronide (3MG) and morphine-6-glucuronide (6MG), with clinical outcomes such as sedation and adverse effects. This report assumes high significance, since such an investigation to titrate postoperative patients to a fixed desired clinical efficacy outcome has hitherto been not performed in patients who underwent postoperative pain managemnt. Moreover, the intravenous titration option used in the study provided a clean collection of pharmacokinetic surrogate data of morphine along with its metabolites without the issue of absorption and/or oral bioavailability setback if morphine was given by oral route. However, the various pharmacokinetic surrogates used in this study was found insufficient to distinguish the clinical effects. Given the complicated pharmacokinetic and pharmacodynamic profiles of morphine and its metabolites (6MG and 3MG), this commentary provides some thoughts to seek answers for this interesting dilemma. © 2013 Informa Healthcare USA, Inc.


PubMed | Suramus Biopharm
Type: Journal Article | Journal: European journal of drug metabolism and pharmacokinetics | Year: 2010

Recent evidences suggest that genetic CYP2C19 polymorphism plays a role in the development of treatment resistance for clopidogrels antiplatelet therapy. This short communication puts forward some strategies that could be potentially used to overcome the genetic polymorphism associated hurdles. While there is some established evidence for an induction strategy and design of chemical structure, the proposed dosing input strategy is speculative in nature. Such thought process and novel explorations are important for delivering medicines in genetically and ethnically diverse populations.


PubMed | Suramus Biopharm
Type: Journal Article | Journal: Xenobiotica; the fate of foreign compounds in biological systems | Year: 2010

Baicalin was extensively researched for utility in a number of therapeutic areas owing to its anti-inflammatory, anti-oxidant, anti-bacterial, and anti-cancer properties. A number of preclinical studies, in vitro work, and mechanistic studies were performed to understand the absorption, distribution, metabolism, and excretion profiles of baicalin. The absorption of baicalin involved several complexities: the restriction to two distant sites; the conversion of baicalin to baicalein; the possible role of transporter(s); and enhanced absorption due to breakdown of conjugates by beta-glucuronidase. Limited distribution data suggest that baicalin reached several sites such as the brain, eye lens, thymus, etc. Hepatobiliary recycling also served as a distribution phase for sustained delivery of baicalin. Metabolism data suggest the rapid conversion of baicalin to baicalein, which was extensively subjected to Phase 2 metabolism, conjugates baicalein glucuronide/sulfate have been identified. Limited excretion data suggest involvement of renal and faecal routes--glucuronide and sulfate conjugates were excreted in urine and faeces (via biliary excretion). The published data on baicalin suggest imminent challenges for developing baicalin and/or during co-administration with other agents. These challenges are absorption related (transporter or changes in the microenvironment), metabolism related (CYP2B6 induction and/or CYP2E1 inhibition), and excretion/efflux related (competitive biliary pathway and/or OATP1B1 transport).


PubMed | Suramus Biopharm
Type: Journal Article | Journal: Arzneimittel-Forschung | Year: 2011

In the evolving paradigm of drug development it is a reasonable strategy to avoid and/or anticipate potential risks in drug development for select drugs by performing in vitro and/or preclinical studies in appropriate animal models. The availability of acute renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic disposition of drugs and associated metabolites in conditions that mimic the pathophysiology of the disease in humans. Such studies may help in drug(s) selection for development, differentiating certain drug classes, and/or arriving at a dose strategy decision in the clinic. Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol (CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The published pharmacokinetic disposition data has unequivocally suggested that ARF conditions leads to decreased renal elimination of the drug and associated metabolites; however, the influence on the overall body clearance is dependent on the propensity of the contribution of renal versus non-renal mechanisms of elimination. In the case studies assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35% of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered exposure, in ARF rat models relative to control rats. Interestingly, ARF can have an overall impact on drug absorption, distribution, metabolism, local transport and biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted with caution during ARF since there is the potential for competiting pathways to co-exist. For instance, due to reduced renal elimination as a result of kidney insult caused by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism. However, there may be instances where uraemic toxins floating in the circulation may block the metabolism and/ or may also retard the absorption process. This review covers: 1) an illustration of a number of case studies providing tabulated information on the key altered pharmacokinetic parameters observed in ARF and the hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption, distribution, metabolism, excretion and efflux transport related changes observed during ARF; 3) a general framework for drug development strategies and 4) a succinct discussion on the overall perspectives of the applicability of ARF rat models.

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