Bioavailability testing assessment

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

Given the overwhelming influence of the physical properties of skin in determining bioavailabilities via the dermal route, assessment of dermal penetration is one area in metabolism and toxicology where in vitro methods can be effectively used to predict in vivo results and to screen chemicals. Apparatus and equipment exist that one can use to maintain sections of skin (obtained from euthanized animals or from human cadavers or surgical discard) for such experiments (Holland et al., 1984). These apparatus are set up to maintain the metabolic integrity of the skin sample between two reservoirs the one on the stratum comeum side, called the application reservoir and the one on the subcutaneous side, called the receptor reservoir. One simply places radiolabeled test material in the application reservoir and collects samples from the receptor fluid at various time points. 

Technical information based on in vivo standards and specifications are generally incorporated in various official compendia. Hence, in order to record a legitimate assessment of bioavailability, in vivo test is an absolute necessity and the relative data obtained therefrom should form an integral part of the standard specifications in the offcial standard. 

Dissolution is also used to identify bioavailability (BA) problems and to assess the need for further BE studies relative to scale-up and post-approval Changes (SUPAC), where it functions as a signal of bioinequivalence. In vitro dissolution studies for all product formulations investigated (including prototype formulations) are encouraged, particularly if in vivo absorption characteristics can be defined for the different product formulations. With such efforts, it may be possible to achieve an in vitro/in vivo correlation. When an in vitro correlation or association is available, the in vitro test can serve not only as a quality control (QC) specification for the manufacturing process, but also as an indicator of in vivo product performance. 

Schuirmann, D. J. A Comparison of the Two One-Sided Tests Procedure and the Power Approach for Assessing the Equivalence of Average Bioavailability. J. Pharmacol. Biopharm., 15, 1987, 657-680. 

Conceptually, SPMD data fills a gap between exposure assessments based on direct analytical measurement of total residues in water and air, and the analysis of residues present in biomonitoring organisms. SPMDs provide a biomimetic approach (i.e., processes in simple media that mimic more complex biological processes) for determining ambient HOC concentrations, sources, and gradients. Residues accumulated in SPMDs are representative of their environmental bioavailability (see Section 1.1.) in water and air and the encounter-volume rate as defined by Landrum et al. (1994) is expected to be proportional to the uptake rate. SPMD-based estimates of water concentrations can be readily compared to aquatic toxicity data (generally based on dissolved phase concentrations) and SPMD extracts can be used to screen for toxic concentrations of HOCs using bioassays or biomarker tests. 

Shigenaka, G. and Henry, C.B. Jr. 1995, Use of Mussels and Semipermeable Membrane Devices To Assess Bioavailability of Residual Polynuclear Aromatic Hydrocarbons Three Years After the Exxon Valdez Oil Spill. In Exxon Valdez Oil Spill Fate and Effects in Alaskan Waters Wells, P.G., Butler, J.N., Hughes, J.S, Eds. American Society for Testing and Materials Philadelphia, PA. pp. 239-260. 

Sufficient bioavailability must be achieved by the chosen formulation with an appropriate selection of excipients. In general, dissolution rate tests and pharmacokinetic studies are used to assess the bioavailability of the drug product. 

Small-scale in vitro test systems may now be employed to assess biopharmaceutical properties or the drug s potential behaviour after in vivo administration. For example, drug penetration through monolayers of epithelial cells in tissue culture can be used to examine bioavailability. The drug s metabolism can be studied in vitro using hepatic microsomes and potentially toxic metabolites identified before problems arise in vivo Although not absolute, these tests... 

Pharmacokinetic mettiods used to assess the bioavailability of two Ca salts used to fortify OJ. Subjects tested 3x s, 2x s witti one fortification, and lx wifii file other (random sequence) 4-week wadiout between treatments... 

Martini and Wood (2002) tested the bioavailability of 3 different sources of Ca in 12 healthy elderly subjects (9 women and 3 men of mean SEM age 70 3 and 76 6 years, respectively) in a 6-week crossover trial conducted in a Human Study Unit. Each Ca source supplied 1000 mg Ca/day and was ingested for 1 week with meals (as 500 mg Ca 2x/day), thus contributing to a high-Ca intake (1300 mg Ca/day). A low-Ca intake (300 mg Ca/day strictly from the basal diet) was adhered to for 1 week in-between each treatment. The Ca sources included skim milk, CCM-fortified OJ, and a dietary supplement of CaCOa. Assessment parameters were indirect measures predicted to reflect the relative bioavailability of Ca postprandially via an acute PTH suppression test (hourly for 4h). Longer-term responses to Ca supplementation were assessed via a number of urinary and serum hormone, mineral, and bone resorption biomarkers (i.e., vitamin D, Ca, phosphorus, and collagen t) e 1 N-telopeptide cross-links). 

The effecf of fhe source of Ca on fhe magnifude of Ca-Fe interactions in vivo was assessed in rodents (Smith, 1988), using a whole body radioisotopic retention test as an endpoint to determine true iron bioavailability (i.e., Fe that is absorbed and utilized). A single 50 gg liquid dose of Fe-labeled FeCla was administered by oral gavage to rats at a Ca Fe ratio of 60 1 and 120 1 fo replicate a human iron intake of 15 mg/day and a Ca intake of 800 mg/day or 1600 mg/day, respectively. Ca sources included CaCOa, Ca Phosphate (CaP), bone meal, and Ca hydroxyapatite (CaHA), while the control dose contained no Ca and was normalized to represent 100% Fe retention for comparison purposes. Isotope counts were performed immediafely after dosing (to measure 100% retention) and subsequent counts over 6 days were divided by the 100% count to estimate Fe retention. For CaCOa, Fe retention was 68% at a Ca Fe ratio of 60 1, and only declined a furfher 2% when the ratio was increased to 120 1. Fe retention values for ofher forms of Ca at a 60 1 Ca Fe ratio were as follows 77% for bone meal, 89% for CaP, and 99% for CaHA. Fe retention decreased in response to the higher Ca Fe ratio of 120 1 (i.e., Fe retention in the presence of bone meal, CaHA, and CaP was 49%, 72%, and 78%, respecfively). This is indicative of a dose-response effect of Ca on Fe retention. This sfudy also underscored fhe importance of the source of Ca in relation fo Fe refenfion. 

Schuirmann DJ (1987) A comparison of two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability Journal of Pharmacokinetics and... 

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