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Clinical Pharmacokinetics Aug 1989Although spinal cord injury is a catastrophic affliction with numerous victims and a variety of physiological manifestations, the associated disarray in physiology has... (Review)
Review
Although spinal cord injury is a catastrophic affliction with numerous victims and a variety of physiological manifestations, the associated disarray in physiology has yet to be systematically or comprehensively studied as a probable cause for altered pharmacokinetics. A significant increase in the volume of distribution of drugs such as the aminoglycosides (gentamicin, amikacin, tobramycin), which are highly distributed into the extracellular fluid space and minimally biotransformed, may be anticipated in patients with chronic spinal cord injury. Changes in total body clearance have also been observed for some of these medications. The influence of the pathophysiology of spinal cord injury on gastrointestinal motility appears to be reflected in an impairment in the bioavailability of drugs [theophylline, paracetamol (acetaminophen), doxycycline] which are passively absorbed and which require an intact postprandial gastric emptying to ensure efficient absorption. For theophylline, the impairment in gastrointestinal absorption appears to be directly proportional to both the magnitude of the impairment in gastric emptying and to the neurological level of the injury. Metoclopramide, a gastrointestinal prokinetic drug, has been shown to be extremely effective in normalising the impaired postprandial gastric emptying that characterises spinal cord injury. The systemic absorption of 2 antibiotics (gentamicin and cefotiam) injected into paralysed muscle is also impaired in patients with spinal cord injury, suggesting that a decrease in therapeutic efficacy attributable to this mode of administration may be anticipated. Despite the multiplicity of drugs commonly prescribed for patients with this injury, little is known about the influence of this illness on either bioavailability or postabsorptive pharmacokinetics. For drugs which are biotransformed and which have a relatively small volume of distribution (theophylline, lorazepam, ranitidine), single-dose intravenous pharmacokinetic profiles in patients with spinal cord injury are indistinguishable from the drug disposition profiles characteristic of healthy control populations. It may be inferred, then that the influence of the pathophysiology of spinal cord injury on drug disposition is greatest on those drugs which are the least biotransformed and most likely to be distributed into the increased extracellular fluid volume which is characteristic of patients with this disability.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Biological Availability; Drug Therapy; Humans; Pharmacokinetics; Spinal Cord Injuries; Tissue Distribution
PubMed: 2673605
DOI: 10.2165/00003088-198917020-00004 -
Clinical Pharmacokinetics Dec 2000Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique... (Review)
Review
Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.
Topics: Adult; Aged; Aging; Area Under Curve; Biotransformation; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intestinal Absorption; Male; Pravastatin; Sex Characteristics; Tissue Distribution
PubMed: 11192473
DOI: 10.2165/00003088-200039060-00002 -
Clinical Calcium 2016Pharmacological outcome and a certain side effects of therapeutic drugs generally depend on concentration of the drugs and/or their active metabolites in the body.... (Review)
Review
Pharmacological outcome and a certain side effects of therapeutic drugs generally depend on concentration of the drugs and/or their active metabolites in the body. Physiologically-based pharmacokinetics is quantitative tool to understand the drug concentration in the body. Drug efficacy is sometimes affected by subjective factors and cannot be clearly quantified. Even in such cases, it could be possible to quantitatively understand possible pharmacological events occurred in the patients by understanding pharmacokinetics of the corresponding drug. Here, we have attempted to summarize the basis of physiologically-based pharmacokinetics to understand which factors will determine drug concentration in the body and how to predict/speculate the drug concentration in the body in a quantitative manner. For easier understanding by the readers, we introduce some examples of pharmacokinetic property of several osteoporosis drugs.
Topics: Biological Availability; Drug-Related Side Effects and Adverse Reactions; Humans; Intestinal Absorption; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 27777386
DOI: No ID Found -
European Review For Medical and... 2002Phamacokinetics is proposed to study the absorption, the distribution, the biotransformations and the elimination of drugs in man and animals. A single kinetic profile... (Review)
Review
Phamacokinetics is proposed to study the absorption, the distribution, the biotransformations and the elimination of drugs in man and animals. A single kinetic profile may be well summarized by Cmax, Tmax, t 1/2 and AUC and, having more than one profile, 8 parameters at least, the mean and standard deviation of these parameters, may well summarize the drug kinetics in the whole population. A more carefull description of the data can be obtained interpolating and extrapolating the drug concentrations with some mathematical functions. These functions may be used to reduce all the data in a small set of parameters, or to verify if the hypotheses incorporated in the functions are confirmed by the observations. In the first case, we can say that the task is to get a simulation of the data, in the second to get a model. The functions used to interpolate and reduce the pharmacokinetic data are the multiexponential functions and the reference models are the compartmental models whose solutions are just the multiexponential functions. Using models, new meaningfull pharmacokinetic parameters may be defined which can be used to find relationships between the drug kinetic profile and the physiological process which drive the drug absorption, distribution and elimination. For example, compartmental models allow to define easily the clearance which is dependent on the drug elimination process, or the volume of distribution which depends on the drug distribution in the tissues. Models provide also an easy way to get an estimate of drug absorption after extravasculare drug administration (bioavailability). Model building is a complex multistep process where, experiment by experiment and simulation by simulation, new hypothesis are proven and disproven through a continuous interaction between the experimenter and the computer.
Topics: Algorithms; Animals; Area Under Curve; Biological Availability; Half-Life; Humans; Models, Biological; Pharmacokinetics; Research
PubMed: 12708608
DOI: No ID Found -
Clinical Pharmacokinetics Sep 2020There appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic...
There appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic drug use and drug switches. In this article, we describe why we are of the opinion that the current regulatory approach to the evaluation of generic drugs based on average bioequivalence is sufficient to expect therapeutic equivalence in the clinical setting. This has often been debated, specifically as adverse drug reactions related to generic drug switches are regularly reported. We agree that clinical discomfort during a bioequivalent drug switch may indeed be caused by different exposures to the active substance. However, this difference in exposure is not a result of the characteristics or quality of generic drugs; it is caused by the pharmacokinetic within-subject variability of the active substance, i.e., the variability on the bioavailability of the active substance, when comparing two occasions of administration of the same drug product, to the same patient. Therefore, reported clinical discomfort following generic drug use and drug switches does not warrant a change in the regulatory approach to the evaluation of the bioequivalence of generic drugs. Switching from a brand-name drug to currently approved generic drugs, or between different generic drugs, will in principle result in comparable exposure, within boundaries determined by the within-subject variability of the pharmacokinetics of the active substance involved.
Topics: Area Under Curve; Biological Availability; Drug Substitution; Drugs, Generic; Government Regulation; Humans; Therapeutic Equivalency
PubMed: 32557345
DOI: 10.1007/s40262-020-00909-8 -
Pharmacotherapy 1991Although cyclosporine has been in clinical use for more than a decade, many questions persist concerning its pharmacokinetics. Gastric emptying, bile acids, and... (Review)
Review
Although cyclosporine has been in clinical use for more than a decade, many questions persist concerning its pharmacokinetics. Gastric emptying, bile acids, and gastrointestinal motility can influence drug absorption after oral administration, but the relative importance of each of these factors and their interactions as determinants of absorption are not clear. The fraction unbound in plasma has been determined in several studies and may be associated with clinical effects. Biochemical and molecular studies have identified the specific cytochrome P-450 enzymes that metabolize cyclosporine to its primary metabolites. The drug's basic pharmacokinetic profile has been defined and many factors have been identified that can influence clearance, such as age, hepatic function, hematocrit, and lipoprotein concentrations. With the development of sensitive and specific analytical methods, many new cyclosporine metabolites have been identified in humans. The major metabolites are present in relatively high concentrations in human blood and have some immunosuppressive activity in vitro, but their contribution to in vivo immunosuppression is not clear.
Topics: Adolescent; Adult; Biological Availability; Child; Child, Preschool; Cyclosporine; Humans; Liver; Metabolic Clearance Rate; Tissue Distribution
PubMed: 1745619
DOI: No ID Found -
Clinical Pharmacokinetics Jul 1990Since many patients with a wide variety of diseases are nowadays stimulated to adopt a physically active lifestyle, the question of the influence of exercise on the... (Review)
Review
Since many patients with a wide variety of diseases are nowadays stimulated to adopt a physically active lifestyle, the question of the influence of exercise on the pharmacokinetics of drugs has become more and more relevant. Because exercise influences a large number of physiological factors that also determine the pharmacokinetics of drugs, including haemodynamics, metabolism, pH, temperature and gastrointestinal function, it can be expected to have an effect on the pharmacokinetic parameters (absorption, distribution, elimination) of certain agents. However, only a very limited number of studies has been directed towards this issue, and only a very few drugs have been studied. Nevertheless, it is clear that exercise does influence the pharmacokinetics of certain drugs, although the magnitude and direction of the effects vary. This is not surprising in view of the widely differing physicochemical properties of drugs, the many possible--often opposing--effects of exercise on the parameters affecting drug pharmacokinetics and the different types of exercise performed. The chance of a clinically relevant effect of exercise on the pharmacokinetics of a particular drug is largest in those with a steep dose-response curve, a narrow therapeutic range, a need for continuity of therapeutic effectiveness and a relatively short half-life, in combination with intensive exercise of long duration. If untoward drug effects occur during or after exercise, a change in the pharmacokinetics of the drug related to the exercise should be seriously considered as a possible cause.
Topics: Absorption; Exercise; Humans; Kidney; Liver; Pharmacokinetics; Tissue Distribution
PubMed: 2199126
DOI: 10.2165/00003088-199019010-00003 -
The Journal of the Association of... Jan 1992Clinical pharmacology is now a well established discipline. Unlike the yester years when dosage schedules were determined by trial and error, in the present day... (Review)
Review
Clinical pharmacology is now a well established discipline. Unlike the yester years when dosage schedules were determined by trial and error, in the present day selection of dose, dosage interval and route of administration are based on pharmacokinetic and pharmacodynamic principles. The primary utility of pharmacokinetics is to study the process of absorption, distribution, metabolism and elimination of drugs, fundamental for drug action. Individuals show a wide variation in kinetic parameters due to internal and external factors. Sometimes change in one variable may be compensated by change in another variable so that dose need not be altered e.g. metabolism of some drugs is increased in thyrotoxicosis but due to increased protein binding overall dose adjustment may not be required. On the other hand sometimes variations in these parameters can markedly affect the plasma concentrations of and the pharmacological response to drugs e.g. anticonvulsant treatment in oral contraceptive users, phenylbutazone addition in warfarin therapy. Drug concentrations can be measured in plasma, urine or saliva. Equipped with this knowledge the modern physician will be able to make a wiser use of drugs under altered physiological conditions like pregnancy, lactation, infancy, old age and pathological states like renal and liver failure and shock.
Topics: Absorption; Blood Proteins; Drug Administration Routes; Humans; Metabolic Clearance Rate; Models, Biological; Pharmacokinetics; Protein Binding
PubMed: 1634460
DOI: No ID Found -
Clinical Therapeutics Aug 2021A new sustained-release (SR) pregabalin formulation (YHD1119) designed for once-daily dosing has recently been developed to improve patient adherence. This study aimed... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
A new sustained-release (SR) pregabalin formulation (YHD1119) designed for once-daily dosing has recently been developed to improve patient adherence. This study aimed to compare the pharmacokinetics of pregabalin SR and immediate-release (IR) formulations after multiple oral doses and to assess the effect of food on the pharmacokinetic profile of the pregabalin SR formulation after a single dose in healthy individuals.
METHODS
Two clinical trials were conducted: a randomized, open-label, multiple-dose, 2-treatment, 2-period crossover study to evaluate the steady-state pharmacokinetic properties of SR treatment (pregabalin SR 300 mg once daily for 3 days) and IR treatment (pregabalin IR 150 mg twice daily for 3 days) under fed conditions and a randomized, open-label, single-dose, 2-treatment, 2-period, crossover study to evaluate the effect of food intake on the pharmacokinetic properties of the pregabalin SR formulation. Plasma concentrations of pregabalin were measured using LC-MS/MS. The AUC and C for pregabalin were calculated using noncompartmental method and compared between treatments in each study.
FINDINGS
Thirty-one individuals in the bioequivalence study and 23 in the food effect study completed the pharmacokinetic sampling. The geometric mean ratios of C and AUC between the SR and IR formulations were 1.1642 (90% CI, 1.1043-1.2272) and 0.9704 (90% CI, 0.9372-1.0047), respectively. The geometric mean ratios of C and AUC between the SR formulation in the fed state and in the fasted state were 1.6514 (90% CI, 1.3820-1.9732) and 1.7899 (90%CI, 1.4499-2.2097), respectively.
IMPLICATIONS
The bioavailability of the pregabalin SR 300 mg formulation is increased if taken with a high-fat meal. Once-daily pregabalin SR 300 mg is bioequivalent to twice-daily pregabalin IR 150 mg under fed conditions at steady state. The pregabalin SR formulation is expected to improve patient adherence. ClinicalTrials.gov identifiers: NCT02783183 (bioequivalence study) and NCT03191136 (food effect study).
Topics: Area Under Curve; Biological Availability; Chromatography, Liquid; Cross-Over Studies; Delayed-Action Preparations; Healthy Volunteers; Humans; Male; Pregabalin; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency
PubMed: 34256964
DOI: 10.1016/j.clinthera.2021.06.010 -
Drug Metabolism and Drug Interactions 2007Drug stereochemistry has, until relatively recently, been an area of neglected dimensionality with the development of the majority of synthetic chiral drugs as... (Review)
Review
Drug stereochemistry has, until relatively recently, been an area of neglected dimensionality with the development of the majority of synthetic chiral drugs as racemates. This situation has changed in recent years as a result of advances in the chemical technologies associated with the synthesis, analysis and preparative scale resolution of the enantiomers of chiral molecules. As a result of the application of these technologies the potential significance of the differential pharmacodynamic and pharmacokinetic properties of the enantiomers present in a racemate have become appreciated. Many of the processes involved in drug disposition, i.e. absorption, distribution, metabolism and excretion, involve a direct interaction with chiral biological macromolecules, e.g. transporters, membrane lipids and enzymes, and following administration of a racemate the individual enantiomers frequently exhibit different pharmacokinetic profiles and rarely exist in a 1:1 ratio in biological fluids. The magnitude of the differences between a pair of enantiomers observed in their pharmacokinetic parameters tends to be relatively modest in comparison to their pharmacodynamic properties. However, the observed stereoselectivity may be either amplified or attenuated depending on the organisational level, e.g. whole body, organ or macromolecular, the particular parameter represents. Differences in parameters involving a direct interaction between a drug enantiomer and a biological macromolecule, e.g. intrinsic metabolite formation clearance and fraction unbound, tend to be largest, and comparison of parameters reflecting the whole body level of organisation, e.g. half-life, clearance, volume of distribution, may well mask significant stereoselectivity at the macromolecular level. In spite of the recent interest in drug chirality relatively limited pharmacokinetic data are available for the enantiomers of a number of commonly used racemic drugs. Factors influencing the stereo-selectivity of drug disposition include: formulation and route of administration; in vivo stereochemical stability, both chemical and enzymatic; drug interactions, both enantiomeric and with a second drug; disease state; age; gender; race; and pharmacogenetics. As a result of such factors estimation of pharmacokinetic parameters, development of complex pharmacokinetic models and plasma-concentration-effect relationships based on 'total' drug concentrations following administration of a racemate are of limited value and potentially useless.
Topics: Metabolic Clearance Rate; Pharmaceutical Preparations; Pharmacokinetics; Stereoisomerism
PubMed: 17708062
DOI: 10.1515/dmdi.2007.22.2-3.79