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Deutsche Medizinische Wochenschrift... Feb 2015Against the background of reduced susceptibility of many pathogens to available antibacterial agents an optimized dosing of antibiotics is of increasing importance to... (Review)
Review
Against the background of reduced susceptibility of many pathogens to available antibacterial agents an optimized dosing of antibiotics is of increasing importance to avoid therapeutic failures and / or microbial resistance. Consideration of the individual body weight, as well as kidney and liver function of a patient and the pharmacodynamics and pharmacokinetic properties of the antibiotic should enable an individualized dosing. An optimized approach could increase efficacy and safety of an antimicrobial therapy significantly. Aimed studies in overweight patients during the clinical development of a new antibiotic are necessary as a substantial prerequisite for a pharmacokinetically based optimized dosing. Intensive care patients also exhibit major changes in pharmacokinetics of antibiotics due to pathophysiological changes. An increased volume of distribution, an increased clearance and reduced protein binding require treatment with increased doses. On the other hand, in patients with acute renal failure often doses have to be reduced and / or the dosing interval has to be prolonged. Renal function should be assessed on the basis of the creatinine clearance. An estimation with the often applied plasma creatinine-based equations can lead to wrong results in critically ill patients, a directly measured urinary creatinine clearance is a more reasonable procedure. However, so far only few prospective studies which investigated the effect of alternative dosing strategies on the therapeutic outcome have been published. Certainly, further comprehensive studies are necessary.
Topics: Anti-Bacterial Agents; Biological Availability; Critical Care; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Microbial; Humans; Kidney Failure, Chronic; Metabolic Clearance Rate; Obesity
PubMed: 25704524
DOI: 10.1055/s-0041-100443 -
Nutrients Nov 2022Succinic acid is widely used as a food additive, and its effects on sepsis, cancer, ataxia, and obesity were recently reported. Dietary drug exposure studies have been...
Succinic acid is widely used as a food additive, and its effects on sepsis, cancer, ataxia, and obesity were recently reported. Dietary drug exposure studies have been conducted to evaluate the in vivo efficacy of succinic acid, but limited pharmacokinetic information is available. Therefore, this study evaluated the pharmacokinetic profiles and tissue distribution of succinic acid following a single intravenous or oral dose. A surrogate analyte, succinic acid-C (CSA), was administrated to distinguish endogenous and exogenous succinic acid. The concentration of CSA was determined by a validated analytical method using mass spectrometry. After a 10 mg/kg intravenous dose, non-compartmental pharmacokinetic analysis in plasma illustrated that the clearance, volume of distribution, and terminal half-life of CSA were 4574.5 mL/h/kg, 520.8 mL/kg, and 0.56 h, respectively. Oral CSA was absorbed and distributed quickly (bioavailability, 1.5%) at a dose of 100 mg/kg. In addition, CSA exposure was the highest in the liver, followed by brown adipose tissue, white adipose tissue, and the kidneys. This is the first report on the pharmacokinetics of succinic acid after a single dose in mice, and these results could provide a foundation for selecting dosing regimens for efficacy studies.
Topics: Mice; Animals; Tissue Distribution; Succinic Acid; Administration, Oral; Biological Availability; Administration, Intravenous
PubMed: 36432443
DOI: 10.3390/nu14224757 -
Revue Des Maladies Respiratoires Jun 2002Physiological changes that occur in the aging process may directly affect drug pharmacokinetics. In the absence of disease or other pathologic conditions, age-related... (Review)
Review
Physiological changes that occur in the aging process may directly affect drug pharmacokinetics. In the absence of disease or other pathologic conditions, age-related changes in pharmacokinetics principally affect drug absorption, distribution, metabolism or elimination. One factor that does change consistently with age is renal clearance, consequently a common pharmacokinetic change is reduced drug clearance, especially for drugs excreted largely unchanged by the kidneys. Alteration of the pharmacokinetics of drugs in the elderly may necessitate adjustment of dosages to prevent toxicity or inadequate therapy. As a broad generalization, dosage should be reduced in elderly patients, reflecting the general decline in body function with age.
Topics: Absorption; Age Factors; Aged; Humans; Tissue Distribution
PubMed: 12161702
DOI: No ID Found -
Current Drug Metabolism May 2012In recent years, many researchers have paid more and more attentions on the use of Nanotechnology. Solid lipid nanoparticles (SLNs) are emerged as a promising... (Review)
Review
In recent years, many researchers have paid more and more attentions on the use of Nanotechnology. Solid lipid nanoparticles (SLNs) are emerged as a promising alternation herein to emulsions, liposomes, microparticles and polymeric nanoparticles for their advantages. As promising drug carrier systems, SLNs are valuable for nanomedicine and have been widely used as delivery systems mostly for drugs and macromolecules like proteins, oligonucleotides and DNA by various application routes, such as intravenous, oral, duodenalous, intramuscular, pulmonary, intranasal, ocular, rectal and intraperitoneal administrations. It has been shown that SLNs can increase bioavailability, alter pharmacokinetic parameters and tissue distribution of the drug loaded. In this review, we will primarily focus on the absorption, pharmacokinetics and disposition properties of SLNs for their possible applications in drug delivery.
Topics: Absorption; Animals; Drug Carriers; Humans; Lipids; Nanoparticles; Tissue Distribution
PubMed: 22443539
DOI: 10.2174/138920012800166553 -
Der Ophthalmologe : Zeitschrift Der... Feb 2014A broad spectrum of anti-inflammatory drugs with different mechanisms is available for the treatment of intraocular inflammation. Corticosteroids are the mainstay of... (Review)
Review
A broad spectrum of anti-inflammatory drugs with different mechanisms is available for the treatment of intraocular inflammation. Corticosteroids are the mainstay of therapy. Mechanisms of action are quite well understood for most drugs in particular taken from animal research studies. However, pharmacokinetic evidence for treatment of ocular disease is generally limited for the human eye and especially for ocular inflammation. The bioavailability of a particular drug in an inflamed eye is expected to be faster due to a barrier breakdown. Therefore, intraocular level of effective substances should be lowered more rapidly than in a non-inflamed eye due to improved drainage. This article reviews current knowledge firstly about local, regional and systemic anti-inflammatory therapy of uveitis and finally on immuosuppressive systemic therapy.
Topics: Administration, Ophthalmic; Biological Availability; Humans; Immunosuppressive Agents; Injections, Intra-Arterial; Injections, Intravenous; Metabolic Clearance Rate; Models, Biological; Ocular Absorption; Uveitis
PubMed: 24337343
DOI: 10.1007/s00347-013-2933-8 -
Clinical Pharmacokinetics 2003Biologic differences exist between men and women that can result in differences in responses to drugs. Both pharmacokinetic and pharmacodynamic differences between the... (Review)
Review
Biologic differences exist between men and women that can result in differences in responses to drugs. Both pharmacokinetic and pharmacodynamic differences between the sexes exist, with more data on pharmacokinetic differences. On average, men are larger than women. Body size differences results in larger distribution volumes and faster total clearance of most medications in men compared to women. Greater body fat in women (until older ages) may increase distribution volumes for lipophilic drugs in women. Total drug absorption does not appear to be significantly affected by sex although absorption rates may be slightly slower in women. Bioavailability after oral drug dosing, for CYP3A substrates in particular, may be somewhat higher in women compared to men. Bioavailability after transdermal drug administration does not appear to be significantly affected by gender; nor does protein binding. Renal processes of glomerular filtration, tubular secretion, and tubular reabsorption appear to be faster in men compared to women whether considered on a mg/kg basis or total body weight basis. Algorithms to estimate glomerular filtration rate incorporate sex as a factor; some also include weight. For hepatic processes, drugs metabolized by Phase I metabolism (oxidation, reduction, and hydrolysis via cytochrome P450's 1A, 2D6, 2E1), Phase II conjugative metabolism (glucuronidation, conjugation, glucuronyltransferases, methyltransferases, dehydrogenases) and by combined oxidative and conjugation processes are usually cleared faster in men compared to women (mg/kg basis). Metabolism by CYP2C9, CYP2C19, and N-acetyltransferase, appear to be similar in men and women (mg/kg). Clearance of p-glycoprotein substrates appear to be similar in men and women. In contrast, total clearance of a number of CYP3A substrates appear to be mildly or moderately faster (mg/kg) in women compared to men. The clinical significance of reported differences warrants consideration. Clearance reported on a per kg basis directly addresses organ or enzyme clearance. The difference in size between men and women means translating these results to clinical dosage rates should include an adjustment for body size. Unfortunately, this is not standard. Reports of sex differences that persist after considering weight may warrant further dosage adjustments. In addition, investigations are often performed in healthy fasting individuals yet medications are prescribed to patients with confounding influences of disease, co-medications, diet, and social habits. The relative role of sex on pharmacokinetics as compared to genetics, age, disease, social habits and their potential interactions in the clinical setting is not yet fully known but should be routinely considered and further studied.
Topics: Animals; Biological Availability; Female; Humans; Male; Metabolic Clearance Rate; Pharmaceutical Preparations; Pharmacokinetics; Sex Characteristics; Tissue Distribution
PubMed: 12537512
DOI: 10.2165/00003088-200342020-00001 -
Revue Des Maladies Respiratoires Nov 2004Physiological changes that occur in the aging process may directly affect drug pharmacokinetics. In the absence of disease or other pathologic conditions, age-related... (Review)
Review
Physiological changes that occur in the aging process may directly affect drug pharmacokinetics. In the absence of disease or other pathologic conditions, age-related changes in pharmacokinetics principally affect drug absorption, distribution, metabolism or elimination. One factor that does change consistently with age is renal clearance, consequently a common pharmacokinetic change is reduced drug clearance, especially for drugs excreted largely unchanged by the kidneys. Alteration of the pharmacokinetics of drugs in the elderly may necessitate adjustment of dosages to prevent toxicity or inadequate therapy. As a broad generalization, dosage should be reduced in elderly patients, reflecting the general decline in body function with age.
Topics: Absorption; Aged; Aging; Humans; Pharmacokinetics; Tissue Distribution
PubMed: 15803535
DOI: No ID Found -
Biopharmaceutics & Drug Disposition Jan 1994Clinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change... (Review)
Review
Clinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change over the therapeutic dose range. However, dose-dependent pharmacokinetics have been reported more frequently in preclinical studies, particularly in toxicity studies, where high doses are often employed. This review highlights the major types of dose-dependent pharmacokinetics with unique examples. Before setting out on a pivotal subchronic and chronic toxicity study of a new drug, a pilot study is often performed to establish a dose range in which a reasonable relationship between plasma AUC and dosage exists to ensure sufficient exposure of animals to the drug. Theoretical bases and possible causes of dose-AUC disproportionality are discussed. Factors affecting the distribution and elimination of drugs and causes of dose-dependent tissue distribution and elimination are also discussed. Often, the non-linear kinetics complicate the design of dosage regimens and prediction of efficacy and toxicity. Thus, an understanding of the influence of dose on the pharmacokinetics is important in the evaluation of the efficacy and toxicity of new drugs.
Topics: Absorption; Administration, Oral; Animals; Blood Proteins; Dose-Response Relationship, Drug; Humans; Liver; Pharmacokinetics; Protein Binding; Tissue Distribution
PubMed: 8161713
DOI: 10.1002/bdd.2510150102 -
Clinical Pharmacology in Drug... Jun 2022This study aimed to evaluate the bioequivalence of 2 amlodipine besylate tablet formulations, a generic formulation and an original formulation, and to investigate their... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to evaluate the bioequivalence of 2 amlodipine besylate tablet formulations, a generic formulation and an original formulation, and to investigate their pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, single-dose, crossover, dual-period study and was divided into fasting and postprandial human bioequivalence trials. In the first trial after overnight fasting, 28 subjects were given 5-mg amlodipine besylate tablets via oral administration, and blood specimens were obtained up to 144 hours after dosing; another 28 subjects had a high-fat meal 1 hour before drug administration and proceeded the same as the fasting trial. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration, log AUC from time 0 to infinity, and log peak concentration. The plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The safety was assessed throughout the study. The results show that no significant differences were observed between the pharmacokinetic profiles of the test and reference amlodipine besylate tablets in the fasting and postprandial trials. The 90%CIs of the peak concentration, AUC from time 0 to the last quantifiable concentration and AUC from time 0 to infinity of amlodipine in the 2 trials were within the commonly accepted bioequivalence criteria of 80% to 125%. Compared with the pharmacokinetic parameters of the fasting and postprandial trials, food had no significant effect on exposure of amlodipine besylate. There was no significant difference in safety statistical results between the 2 groups. The results suggest that generic and original amlodipine besylate tablets are bioequivalent with similar safety profiles.
Topics: Amlodipine; Area Under Curve; Cross-Over Studies; Drugs, Generic; Healthy Volunteers; Humans; Tablets; Therapeutic Equivalency
PubMed: 34981666
DOI: 10.1002/cpdd.1064 -
Clinical Pharmacokinetics Aug 1992The pharmacokinetics of drugs may be altered following an overdose. The degree of absorption depends on the physical characteristics of the drug; the rate of dissolution... (Review)
Review
The pharmacokinetics of drugs may be altered following an overdose. The degree of absorption depends on the physical characteristics of the drug; the rate of dissolution may delay or broaden peak serum concentrations. The pathophysiological effects of a drug may also limit or augment absorption. Altered distribution of drugs in overdose results from changes in the extent of protein binding and size of the volume of distribution. Saturation of hepatic enzyme systems in overdose is manifested by delayed metabolism or elimination of many drugs; renal elimination of unchanged drug may take on greater importance in this instance. Familiarity with the toxicokinetic profile of a given drug enables the physician to exploit these principles in order to limit toxicity. Delayed or prolonged absorption allows for late decontamination. Multiple doses of activated charcoal are effective in interrupting both entero-enteric and enterohepatic recirculation. Alkalinisation-induced ion trapping enhances renal elimination of unchanged drugs which normally undergo hepatic transformation. For several drugs, chronic overdose due to altered distribution is associated with a greater severity of toxic manifestations despite relatively low serum drug concentrations. Conversely, with some drugs, induction of metabolic pathways may lead to more rapid drug elimination in chronic overdose. Knowledge of the pharmacokinetic alterations which occur in drug overdose enables the physician to predict toxicity with greater accuracy and to institute optimum therapy in a timely manner.
Topics: Absorption; Drug Overdose; Humans; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 1511533
DOI: 10.2165/00003088-199223020-00003