Corrections for Bioavailability

Bioavailability should be considered when assessing compliance of a water body with an EQS, rather than modifying the derivation of the EQS as discussed, unless the EQS is calculated or designed to be calculated on a site-specific basis. Increasingly in the United States, EQSs are being presented as equations or models to be used on a site-specific basis rather than as a national number to be applied broadly thus, bioavailability is addressed within the derivation of the value rather than at the time of compliance comparison. 

When constructing an SSD, it is important to use data for the same range of test conditions (e.g., pH, salinity). For example, PNECs derived for metals should ideally 

Model ecosystem data with small assessment factor 

SSDs based on chronic NOECs (or ECx) with minimum data set or greater plus small or no assessment factor 

Medium assessment factor applied to lowest chronic NOEC from data set of 5 or more species 

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The Vj can be determined easily for the one-compartment model. When t = 0 (the time the drug bolus is introduced), Dq, the amount of drug given and corrected for bioavailability (/), is equal to the amount of drug in the compartment the blood concentration (Co) is... 

Level 3a A baseline bioavailability correction (Level 3a) can be conducted if a BLM for algae, fish or invertebrates is available. Such baseline bioavailability correction, consisting of the application of a conservative bioavailability factor (Bio-F), is applicable if no direct evidence is available to support a cross-reading or if mechanisms of toxicity differ across species within a specific trophic level. This method is based on the calculation of reference NOEC/ECio values (i.e. reference NOEC/ECio dissolved) and normalised NOEC/ECio values for the test organisms for which the bioavailabiUty models were developed under typical site-specific conditions (i.e. site-specific NOEC/ECio bioavaUabie, dissolved). Both normalised toxicity values are compared for every species for which the bioavailability models were developed, and the most conservative value (smallest correction for bioavailability, site - specific NOEC/ECjq HoavailaWe, dissolved v... 

Calculation of bioavailability requires a comparison of the AUcs following a non-intravenous and an intravenous dose, after correction for dose size. Without knowing the bioavaUabU-ity, only apparent clearance and volume of distribution can be calculated, and the ability to make predictions from these values is very limited. 

It can be assumed that the bioavailability of an intravenous dose is 100% and a calculation of oral bioavailability can therefore be obtained by comparison of the AUCs after oral and intravenous administration, after correction for the exact dose ... 

Whole-body isotope retention experiments were performed (via the method described above in the Smith experiment and with confirmed corrections for isotope decay rates), using extrinsically labeled ferric chloride hexahydrate and Ca from CCM (i.e., [ FeJFeCla and [" Ca] CaCl2) to determine the bioavailability of these minerals at an Fe Ca ratio of 1 167 mol/mol. CCM solubility was also assessed via a filtration method. 

Bioavailability determined from blood AUC, corrected for dose. 

Bioavailability determined for cumulative amount excreted in urine (Au) after correcting for dose. 

In the United States as well as in Europe, the use of matrix extrapolation techniques for estimating the bioavailability of toxicants is officially encouraged. An example is the Ohio EPA (1996) recommendation to use hardness-corrected water quality criteria for heavy metals. The EUSES (Jager 2003) computer program of the European Union for predicting the risk of new compounds to be released into the environment corrects for partitioning processes in the calculation for all types of effects. 

The protocols to aggregate compound-specific PAF values to a single risk estimate for a mixture of compounds are derived from common toxicological theories on joint effects of compounds. As already proposed by van Straalen and Bergema (1995), these protocols may be applied after corrections for differences in bioavailability among test media and the actual field conditions have been made, if the necessary information is available. This adaptation to reflect actual exposure is conceptually motivated by the common theory of molecule-receptor interactions, which... 

Bioavailability is defined as the extent - and sometimes also the rate -of drug absorption. For oral therapy, absolute bioavailability is usually determined by comparing the area under the concentration-time curve (AUC) after an oral dose with that after an intravenous dose. Assuming clearance is constant, bioavailability is defined as the ratio of oral to intravenous AUC, corrected for dose, and is expressed as a proportion or a percentage. For example, an oral bioavailability of around 20% means that an oral dose of 100 mg would achieve an exposure equivalent to that of an intravenous dose of 20 mg. For some drugs with low bioavailability due to a high first-pass metabolism, oral dose requirements may be lower in patients with severe hepatic disease due to a reduction in first-pass metabolism in the liver and consequent increase in bioavailability [1]. In contrast, reduced bioavailability of lipophilic drugs may occur in cholestasis and has been reported with ciclosporin, particularly with early formulations [5]. 

Bioavailability (absolute) was based on AUCtopicai/AUCrv, with correction for dose. GFI = glycerol-formal/isopropanol mixture. 

AUC is a frequency distribution of the number of molecules within the body versus time. When measured out to infinity (< ), the AUC value (AUCo a) represents the total drug exposure. Its value is unaffected by the rate of absorption (assuming linear kinetics) but is affected by dose, clearance and bioavailability. Bioavailability is calculated by comparing the total amount of drug in the body (AUC) following administration by a non-i.v. route with that obtained following i.v. administration (100%), corrected for dose. 

A commercially available extended-release capsule (Levsinex TimecapsR) contains small beads of hyoscyamine sulfate which are surrounded by a porous membrane that permits fluids to enter and dissolve the drug. The manufacturer states that 0.375 mg of drug is delivered from a capsule at an approximate rate of 0.125 mg/4 hours. In a crossover study comparing extended-release capsules and conventional tablets, bioavailability (as determined by area under the plasma concentrationtime curve) during the first 4 hours after administration of a single 0.375 mg dose as extended-release capsules, was about 43% that of a single 0.125 mg dose as conventional tablets when the data were corrected for difference in dose (51). 

In ten cases, Che corrected values were less than the uncorrected ones. Because of this inconsistency and because correction does not reduce variability within nor among experiments, attempting to correct for the iron contribution of Che basal ingredients Co Che hematinic response does not seem to improve this assay of iron bioavailability. 

The bioavailability (F), correcting for the fraction absorbed ( Q and fraction escaping intestinal metabolism (fg), is... 

In which soil is arsenic likely to be more mobile and bioavailable (Ignore activity corrections for solution concentrations in this problem.)... 

In 1992, Drejer et al. [31] investigated the pharmacokinetics of intranasal insulin containing a medium-chain phospholipid (didecanoyl-L-alpha-phosphatidylcho-line) as absorption enhancer in 11 normal volunteers. Intranasal insulin was absorbed in a dose-dependent manner with a mean plasma insulin peak 23 7 min after administration. Mean plasma glucose nadir was seen after 44 6min, 20min after intravenous injection. Moreover, intranasal administration of insulin resulted in a faster time-course of absorption than subcutaneous injection, and the bioavailability for the nasal formulation was 8.3% relative to an intravenous bolus injection when plasma insulin was corrected for endogenous insulin production estimated by C-peptide. 

Absolute bioavailability refers to the fraction of the oral dose that is absorbed (i.e., reaches systemic circulation). The fraction absorbed is also defined as F so that Equations 1.14 and 1.27 are equivalent. Absolute bioavailability is shown in Equations 1.27 and 1.28, the latter representing a correction for dose. Each product is tested individually to determine its absolute bioavailability in the subjects. The IV dose becomes a reference for which drug is assumed to be 100% available. On occasion, a solution may be substituted for an IV dosage form providing it is 100% bioavailable (i.e., reaches systemic circulation). 

A classic technique employed in pharmacology and toxicology disposition studies for all routes of administration is the mass balance approach (Riviere, 1999). Mass balance analysis accounts for all of the topically applied dose of the compound, whether it is in the formulation, associated with the skin surface, penetrated into the stratum comeum, distributed into the carcass, or absorbed into and excreted from the blood into urine and feces. In this context, total recovery of 90% of the apphed dose is considered excellent recovery (Schaefer and Redelmeier, 1996). Mass balance studies are conducted by collecting all excreta after topical and parenteral administration. Data from a parenteral route such as intravenous dosing is required to correct for the fraction of absorbed compoimd appearing into the excreta collected if a precise estimate of bioavailability is to be determined and all routes of excretion are not collected (e.g., collection of urine and feces but not expired air) (Riviere, 1999). In such a study, absorption is calculated as follows ... 

Three studies found that intravenous cimetidine also inhibited the clearance of theophylline (given as intravenous aminophylline or sustained-re-lease theophylline). " In one of these, oral and intravenous cimetidine reduced theophylline clearance to the same extent, but when clearance was corrected for the lower bioavailability of the oral cimetidine, oral cimetidine resulted in a greater inhibition than intravenous cimetidine. Another study found that the effects of a continuous 50-mg/hour infusion of cimetidine were similar to those of an intermittent infusion of 300 mg every 6 hours. ... 

The use of drugs not absorbed from the GI tract Charcoal-block methods Correction for drugs of known bioavailability Indirect methods, such as 30-min urinary excretion... 

In order to avoid the need for activated charcoal, some investigators calculate the lung dose by correcting for the GI contribution, using oral bioavailability data (90). This can be applied only to drugs adnfinistered to subjects in whom the oral bioavailability has been clearly established in the subject group. 

The lack of hard evidence about the extent of supplementation required in pregnancy prompted the development of a laboratory-based assessment of metabolic turnover, which involved the assay of total daily folate catabolites (along with intact folate) in the urine of pregnant women. The rationale of the procedure was that this catabolic product represents an ineluctable daily loss of folate, the replacement of which should constitute the daily requirement. Correcting for individual variation in catabolite excretion and the bioavailability of dietary folate, the recommended allowances based on this mode of assessment are in close agreement with the latest recommendations of the USA/Canada and FAO/WHO. The data produced by the catabolite-excretion method may provide a useful adjunct to current methods... 

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