Friday, March 18, 2011
Friday, March 11, 2011
See few articles below about drug metabolism
and mitochondria.
Clearly, prevention is paramount, secondly, look at other options of dealing with health issues, and thirdly, be responsible for your own health issues. Read up on the pharmacological content of prescribed meds, validity, the science, effective?, side effects and adverse reactions. Read about what other patients themselves experienced, over a period of time. Most who suffer ill health do not make the association with off the counter meds and/or prescribed meds. It takes longer than a few weeks or months, sometimes years for inflammation to progress.
Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs
1. Bradley L. Urquhart, PhD
2. Rommel G. Tirona, PhD
3. Richard B. Kim, MD
1.
From the Division of Clinical Pharmacology, Department of Medicine (Dr Urquhart, Dr Tirona, Dr Kim), and the Department of Physiology & Pharmacology (Dr Tirona), University of Western Ontario, London, Ontario, Canada.
1. Address for correspondence: Richard B. Kim, MD, Division of Clinical Pharmacology, London Health Sciences Centre—University Hospital, Room ALL-152, 339 Windermere Road, London, Ontario N6A 5A5, Canada; e-mail: richard.kim@lhsc.on.ca.
Abstract
Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. An important determinant of such interindividual differences in drug response is variability in the expression of drug-metabolizing enzymes and/or transporters at sites of absorption and/or tissue distribution. Variable drug-metabolizing enzyme and transporter expression can result in unpredictable exposure and tissue distribution of drugs and may manifest as adverse effects or therapeutic failure. In the past decade, important new insights have been made relating to the regulatory mechanisms governing the expression of drug-metabolizing enzymes and transporters by ligand-activated nuclear receptors. Specifically, there is compelling evidence to demonstrate that PXR, CAR, FXR, LXR, VDR, HNF4α, and AhR form a battery of nuclear receptors that regulate the expression of many important drug-metabolizing enzyme and transporters. In this review, the authors focus on clinically important drug-metabolizing enzymes such as CYP3A4, CYP2B6, CYP2C9, CYP2C19, UGT1A1, SULT2A1, and glutathione S-transferases and their regulation by nuclear receptors. They also review the nuclear receptor-mediated regulation of drug transporters such as MDR1, MRP2, MRP4, BSEP, BCRP, NTCP, OATP1B3, and OATP1A2. Finally, they outline how the drug development process has been affected by the current understanding of the involvement of nuclear receptors in the regulation of drug disposition genes. http://tinyurl.com/5t5qzcd
I was curious about comparative study for ADRs between Fqs and other antibiotics. Those who are suffering from ADRs, (NOT allergic reactions), from other antibiotics, take note. So yes, many of us, have/had ADRs from non FQs pre/post floxing!! Figures seem to vary, one other study show cephalosporins to be between 19-40%...
Abstract and Introduction
Abstract
Extensive pharmacologic and clinical development of quinolone antimicrobial agents has resulted in improved antimicrobial activity, pharmacokinetic features, toxicity, and drug-drug interaction profiles. Nalidixic acid and other early quinolones had limited use due to poor pharmacokinetics, relatively narrow antimicrobial spectrum of activity, and frequent adverse effects. Beginning with the development of fluoroquinolones, such as norfloxacin and ciprofloxacin, in the 1980s, the agents assumed a greatly expanded clinical role because of their broad antimicrobial spectrum of action, improved pharmacokinetic properties, and more acceptable safety profile. Although the pharmacokinetics and efficacy of the drugs have improved significantly, a major area of continued emphasis is to further reduce the frequency and severity of adverse events and drug-drug interactions. Older agents such as ciprofloxacin and ofloxacin are still extensively prescribed, but the focus of this article is on the newer fluoroquinolones (levofloxacin and other drugs that have been approved or have been under investigation since approximately 1997). http://www.medscape.com/viewarticle/418295
For those who are still keen on taking antibiotics, read about the mitochondria cytoxicity, which means essentially, DNA damage. There are several articles posted on the forum about damage to mitochondria, worse offenders are: antibiotics (Fqs, macrolides, tetracyclines, clyndamicin, Rifamopin), anti-depressants and NSAIDs... This study is well designed and discusses glycation, cell death, lactic acidosis etc. http://aac.asm.org/cgi/reprint/AAC.00729-05v1.pdf
For those of us who are having problems with foods, vits & supps, and metabolozing drugs, read on...
It appears that minute dosage of anything is not being metabolized (for some of us), and reaches a level of toxicity. This can apply to some compounds in some type of foods. This partly explains the inability to metabolize, the aforementioned including environmental pollutants.
"Enzymes that metabolize xenobiotics have historically
been called drug-metabolizing enzymes, although they are
involved in the metabolism of many foreign chemicals to
which humans are exposed. Dietary differences among
species during the course of evolution could account for
the marked species variation in the complexity of the
drug-metabolizing enzymes.
Today, most xenobiotics to which humans are exposed
come from sources that include environmental pollution,
food additives, cosmetic products, agrochemicals, processed
foods, and drugs. In general, these are lipophilic
chemicals, that in the absence of metabolism would not be
efficiently eliminated, and thus would accumulate in the
body, resulting in toxicity. With very few exceptions, all
xenobiotics are subjected to one or multiple pathways that
constitute the phase 1 and phase 2 enzymatic systems. As
a general paradigm, metabolism serves to convert these
hydrophobic chemicals into derivatives that can easily be
eliminated through the urine or the bile."http://books.mcgraw-hill.com/medical/goodmanandgilman/pdfs/CHAPTER3.pdf
and mitochondria.
Clearly, prevention is paramount, secondly, look at other options of dealing with health issues, and thirdly, be responsible for your own health issues. Read up on the pharmacological content of prescribed meds, validity, the science, effective?, side effects and adverse reactions. Read about what other patients themselves experienced, over a period of time. Most who suffer ill health do not make the association with off the counter meds and/or prescribed meds. It takes longer than a few weeks or months, sometimes years for inflammation to progress.
Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs
1. Bradley L. Urquhart, PhD
2. Rommel G. Tirona, PhD
3. Richard B. Kim, MD
1.
From the Division of Clinical Pharmacology, Department of Medicine (Dr Urquhart, Dr Tirona, Dr Kim), and the Department of Physiology & Pharmacology (Dr Tirona), University of Western Ontario, London, Ontario, Canada.
1. Address for correspondence: Richard B. Kim, MD, Division of Clinical Pharmacology, London Health Sciences Centre—University Hospital, Room ALL-152, 339 Windermere Road, London, Ontario N6A 5A5, Canada; e-mail: richard.kim@lhsc.on.ca.
Abstract
Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. An important determinant of such interindividual differences in drug response is variability in the expression of drug-metabolizing enzymes and/or transporters at sites of absorption and/or tissue distribution. Variable drug-metabolizing enzyme and transporter expression can result in unpredictable exposure and tissue distribution of drugs and may manifest as adverse effects or therapeutic failure. In the past decade, important new insights have been made relating to the regulatory mechanisms governing the expression of drug-metabolizing enzymes and transporters by ligand-activated nuclear receptors. Specifically, there is compelling evidence to demonstrate that PXR, CAR, FXR, LXR, VDR, HNF4α, and AhR form a battery of nuclear receptors that regulate the expression of many important drug-metabolizing enzyme and transporters. In this review, the authors focus on clinically important drug-metabolizing enzymes such as CYP3A4, CYP2B6, CYP2C9, CYP2C19, UGT1A1, SULT2A1, and glutathione S-transferases and their regulation by nuclear receptors. They also review the nuclear receptor-mediated regulation of drug transporters such as MDR1, MRP2, MRP4, BSEP, BCRP, NTCP, OATP1B3, and OATP1A2. Finally, they outline how the drug development process has been affected by the current understanding of the involvement of nuclear receptors in the regulation of drug disposition genes. http://tinyurl.com/5t5qzcd
I was curious about comparative study for ADRs between Fqs and other antibiotics. Those who are suffering from ADRs, (NOT allergic reactions), from other antibiotics, take note. So yes, many of us, have/had ADRs from non FQs pre/post floxing!! Figures seem to vary, one other study show cephalosporins to be between 19-40%...
Abstract and Introduction
Abstract
Extensive pharmacologic and clinical development of quinolone antimicrobial agents has resulted in improved antimicrobial activity, pharmacokinetic features, toxicity, and drug-drug interaction profiles. Nalidixic acid and other early quinolones had limited use due to poor pharmacokinetics, relatively narrow antimicrobial spectrum of activity, and frequent adverse effects. Beginning with the development of fluoroquinolones, such as norfloxacin and ciprofloxacin, in the 1980s, the agents assumed a greatly expanded clinical role because of their broad antimicrobial spectrum of action, improved pharmacokinetic properties, and more acceptable safety profile. Although the pharmacokinetics and efficacy of the drugs have improved significantly, a major area of continued emphasis is to further reduce the frequency and severity of adverse events and drug-drug interactions. Older agents such as ciprofloxacin and ofloxacin are still extensively prescribed, but the focus of this article is on the newer fluoroquinolones (levofloxacin and other drugs that have been approved or have been under investigation since approximately 1997). http://www.medscape.com/viewarticle/418295
For those who are still keen on taking antibiotics, read about the mitochondria cytoxicity, which means essentially, DNA damage. There are several articles posted on the forum about damage to mitochondria, worse offenders are: antibiotics (Fqs, macrolides, tetracyclines, clyndamicin, Rifamopin), anti-depressants and NSAIDs... This study is well designed and discusses glycation, cell death, lactic acidosis etc. http://aac.asm.org/cgi/reprint/AAC.00729-05v1.pdf
For those of us who are having problems with foods, vits & supps, and metabolozing drugs, read on...
It appears that minute dosage of anything is not being metabolized (for some of us), and reaches a level of toxicity. This can apply to some compounds in some type of foods. This partly explains the inability to metabolize, the aforementioned including environmental pollutants.
"Enzymes that metabolize xenobiotics have historically
been called drug-metabolizing enzymes, although they are
involved in the metabolism of many foreign chemicals to
which humans are exposed. Dietary differences among
species during the course of evolution could account for
the marked species variation in the complexity of the
drug-metabolizing enzymes.
Today, most xenobiotics to which humans are exposed
come from sources that include environmental pollution,
food additives, cosmetic products, agrochemicals, processed
foods, and drugs. In general, these are lipophilic
chemicals, that in the absence of metabolism would not be
efficiently eliminated, and thus would accumulate in the
body, resulting in toxicity. With very few exceptions, all
xenobiotics are subjected to one or multiple pathways that
constitute the phase 1 and phase 2 enzymatic systems. As
a general paradigm, metabolism serves to convert these
hydrophobic chemicals into derivatives that can easily be
eliminated through the urine or the bile."http://books.mcgraw-hill.com/medical/goodmanandgilman/pdfs/CHAPTER3.pdf
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