Decarbonising Energy End Use Background Paper No.6 Final Report from the NESC Secretariat Ireland and the Climate Change Challenge: Connecting ‘How Much' with ‘How To' Joe Curtin December 2012 Decarbonising Energy End Use Chapter 11. Introduction The coming together of two previously isolated technologies in the 1960s––computers and the communications––had paradigm-shifting consequences for the way economic and social systems operated. Up to the late 1960s the communications system was characterized by centralized switching stations via which communications (telegram and telephone) were routed and users were manually connected. In the new system these hierarchies were flattened, allowing the flow of information to and from each user across various networks. This automated system was governed by a flexible and constantly revised series of protocols that were interpreted by computers at each node .
(anonymous)bioavailability is used to describe the fraction of an administered
reaches the , one of the principal . By definition, when a medication is administered  However, when a medication is administered (such as orally), its bioavailability decreases (due to incomplete absorption and ) or may vary from patient to patient (due to inter-individual variation). Bioavailability is one of the non-intravenous routes of administration.
bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed. method of administration and regulations.
A (often a "[it] is available to cross an organism's from the environment, if the organism has access to the chemical."  In pharmacology, bioavailability is a measurement of the extent to which a drug reaches the systemic circulation. It is denoted by the letter F.
In nutritional sciences
In nutritional sciences, which covers the intake of nutrients and non-drug dietary ingredients, the concept of bioavailability lacks the well-defined standards associated with the pharmaceutical industry. The pharmacological definition cannot apply to these substances because utilization and absorption is a function of the nutritional status and physiological state of the subject, resulting in even greater differences from individual to individual (inter-individual variation). Therefore, bioavailability for dietary supplements can be defined as the proportion of a the substance capable of being absorbed and available for use or storage. In both pharmacology and nutrition sciences, the bioavailability is measured by calculating the , or AUC, of the drug concentration time profile.
Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following the bioavailability of the same drug following intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be dose normalized (e.g. account for different doses or varying weights of the subjects); consequently, the amount absorbed is corrected by dividing the corresponding dose administered.
obtain a plasma drug concentration vs time plot for the drug after both intravenous (IV) and non-intravenous administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the oral route (po) is given below.
Therefore, a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1) while drugs given by other routes usually have an absolute bioavailability of less than one. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability.
Although knowing the true extent of systemic absorption (referred to as absolute bioavailability) is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference, that is, a route of administration that guarantees that all of the administered drug reaches the systemic circulation. Such studies come at considerable cost, not least of which is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as there being potential problems due to solubility limitations. There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailbility information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously. Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution (V) and clearance (CL). Relative bioavailability and bioequivalence
In pharmacology, relative bioavailability measures the bioavailability (estimated as the AUC) of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute 0.05 level of significance For FDA approval, a generic manufacturer must show that the 90% confidence interval for the ratio of the mean response (usually AUC and Cmax) of its product to that of the "Brand Name drug" is within the limits of 0.8 to 1.25 at the 0.05 level of significance. Relative bioavailability is extremely sensitive to drug formulation. Relative bioavailability is one of the measures used to assess between two drug products, as it is the Test/Reference ratio of AUC. The maximum concentration of drug in plasma or serum (Cmax) is also usually used to assess bioequivalence. When Tmax is given, it refers to the time it takes for a drug to reach While the mechanisms by which a formulation affects bioavailability and bioequivalence have been extensively studied in drugs, formulation factors that influence bioavailability and bioequivalence in nutritional supplements are largely unknown. As a result, in nutritional sciences, relative bioavailability or bioequivalence is the most common measure of bioavailability, comparing the bioavailability of one formulation of the same dietary ingredient to Factors influencing bioavailability
The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e. F<1). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect.
Other factors may include, but are not limited to: • Physical properties of the drug (hydrophobicity, pKa, solubility) • The drug formulation (immediate release, excipients used, manufacturing methods, modified release - delayed release, extended release, sustained release, etc.) • Gastric emptying rate • Interactions with other drugs/foods: • Interactions with other drugs (e.g. antacids, alcohol, nicotine) • Transporters: Substrate of an transporter? (e.g. P-glycoprotein) • Enzyme induction (increase rate of metabolism). e.g. (antiepileptic) induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4 • Enzyme inhibition (decrease rate of metabolism). e.g. grapefruit juice inhibits CYP3A --> higher nifedipine • Individual Variation in Metabolic Differences • Age: In general, drugs metabolized more slowly in fetal, neonatal, and geriatric populations • Phenotypic differences, enterohepatic circulation, diet, gender.
• Disease state Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In drug clinical trials, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.
Bioavailability of drugs versus dietary supplements
In comparison to drugs, there are significant differences in dietary supplements that impact the evaluation of their bioavailability. These differences include the following: the fact that nutritional supplements provide benefits that are variable and often qualitative in nature; the measurement of nutrient absorption lacks the precision; nutritional supplements are consumed for prevention and well-being; nutritional supplements do not exhibit characteristic dose-response curves; and dosing intervals of nutritional supplements, therefore, are not critical in contrast to drug In addition, the lack of defined methodology and regulations surrounding the consumption of dietary supplements hinders the application of bioavailability measures in comparison to drugs. In clinical trials with dietary supplements, bioavailability primarily focuses on statistical descriptions of mean or average AUC differences between treatment groups, while often failing to compare or discuss their standard deviations or inter-individual variation. This failure leaves open the question of whether or not an individual in a group is likely to experience the benefits described by the mean-difference comparisons. Further, even if this issue were discussed, it would be difficult to communicate meaning of these inter-subject variances to consumers and/or their physicians.
Nutritional science: reliable and universal bioavailability
One way to resolve this problem is to define "reliable bioavailability" as positive bioavailability results (an absorption meeting a predefined criteria) that include 84% of the trial subjects and "universal bioavailability" as those that include 98% of the trial subjects. This reliable-universal framework would improve communications with physicians and consumers such that, if it were included on products labels for example, make educated choices as to the benefits of a formulation for them directly. In addition, the reliable-universal framework is similar to the construction of confidence intervals, which statisticians have long offered as one potential solution for dealing with small samples, violations of statistical assumptions or large standard deviations.  Griffin, J.P. The Textbook of Pharmaceutical Medicine (6th Ed.). New Jersey: BMJ Books. ISBN 9781405180351  Factors Influencing the Measurement of Bioavailability, Taking Calcium as a Model. Robert P. Heaney. J. Nutr. (2001) 131:1344S-1348S  Semple KT, Doick KJ, Jones KC, Burauel P, Craven A, Harms H (2004). "Defining bioavailability and bioaccessibility of contaminated soil Environ. Sci. Technol. 38 (12): 228A–231A.
doi:10.1021/es040548w. PMID 15260315.
 Shargel, L.; Yu, A.B. (1999). Applied biopharmaceutics & pharmacokinetics (4th ed.). New York: McGraw-Hill. ISBN 0-8385-0278-4  Heaney RP (2001). "Factors Influencing the Measurement of Bioavailability, Taking Calcium as a Model". J. Nutr. 131 (4 Suppl):
 Srinivasan VS (2001). "Bioavailability of Nutrients: A Practical Approach to In Vitro Demonstration of the Availability of Nutrients in Multivitamin-Mineral Combination Products". J. Nutr. 131 (4 Suppl): 1349S-1350S. PMID 11285352.
 The use of Isotopes in the Determination of Absolute Bioavailability of Drugs in Humans. Graham Lappin, Malcolm Rowland, R. Colin Garner. Expert Opin. Drug Metab. Toxicol. (2006) 2(3)  Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Graham Lappin, Lloyd Stevens. Expert Opin. Drug Metab. Toxicol. (2008) 4(8):1021-1033  Hoag SW, Hussain AS (2001). "The Impact of Formulation on Bioavailability: Summary of Workshop Discussion.". J. Nutr. 131 (4 Suppl):
 Kagan D, Madhavi D, Bank G, Lachlan K (2010). ""Universal" and "Reliable" Bioavailability Claims: Criteria That May Increase Physician Confidence in Nutritional Supplements.". Natural Medicine Journal. 2 (1): 1–
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