Maximum absorbable dose

The concept of maximum absorbable dose (MAD) relates drug absorption to solubility via [27, 28] ... 

Semiquantitative schemes, like the maximum absorbable dose (MAD) system described by Curatolo [53], can be made more predictive by applying solubilities measured by clinically-relevant protocols and PAMPA permeabilities. 

In the current era with widespread problems of poor solubility [4] a compound (drug) with average permeability and a projected clinical potency of 1 mg kg-1 needs a minimum aqueous solubility of 50-100 jug mL-1 to avoid the use of nonstandard solubility fixing formulation technology. The guidelines published by Pfizer s Curatolo on maximum absorbable dose are an excellent guide for the combination of permeability, solubility and potency required in an orally active drug [8],... 

Keywords Absorption In silico Mixing tank Maximum absorbable dose Mass balance approach Compartmental absorption Transit models... 

The maximum absorbable dose (MAD) can be derived from the mixing tank model as shown by Johnson and Swindell [29], The amount of drug absorbed (Xa) at any time is a function of a first-order absorption constant (Ka) and the amount of dissolved drug (Xd) as described in Eq. 6. 

By integrating Eq. 6, the cumulative amount absorbed can be calculated. If the dose is hypothetically increased to extreme doses, a constant concentration (equal to the thermodynamic solubility of the drug in the intestinal fluids, Cs) could be maintained over the integrated time period. In this case the amount in solution would equal the thermodynamic solubility of the dmg multiplied by the volume present in the intestine (Xd = Cs V) and the maximum absorbable dose (MAD) would be given by Eq. 7 [11, 29],... 

Low or poor aqueous solubility is a relative term. Therefore, the solubility of a compound must be considered together with its dose and permeability. A simple approach to assess oral absorption with a drug substance could be the calculation of its maximum absorbable dose (MAD) 69... 

The formulation was applied with a calibrated wire wound applicator onto a quartz or sodium chloride plate the thickness of the uniform layer was typically between 5 and 10 . Samples were exposed to the laser beam for various durations up to a maximum absorbed dose of 100 mJ cm-2. Except for some specific experiments carried out in a nitrogen saturated reactor, all the irradiations were performed in the presence of air, at room temperature. 

The MEBRF can be operated over a range of flow rates from 60 to 160 gpm. The maximum absorbed dose delivered by the electron beam depends on the flow rate an application requiring a dose of 1290 krad would limit... 

The rate of absorption of 2,k,5-T into the body appeared to be slower after external exposure than after oral administration in humans. Pharmacokinetic modeling indicated 91% of the 2,h,5-T absorbed through the skin would be cleared within 1 week. Measurement of 2,k,5-T excreted in urine of spray crews demonstrated that the maximum absorbed dose is not likely to exceed 0.1 mg per kg of body weight per work day. Urinary excretion provided a more reliable measure of dose than analysis of patches worn by the workers. Exposure was highest in mixers who handled the spray concentrate and in sprayers using backpack equipment. 

When a single dose of a drug is administered orally its plasma concentration increases to a maximum value (Cmax) at /inax before falling with time (Figure 8.9). The increase in plasma concentration occurs as the drug is absorbed. It is accompanied by elimination, which starts from the instant the drug is absorbed. The rate of elimination increases as the concentration of the drug in the plasma increases to the maximum absorbed dose. At this point, the rate of absorption is equal to the rate of elimination. Once absorption ceases, elimination becomes the dominant pharmacokinetic factor and plasma concentration falls. 

A relevant simple model was used to estimate the maximum absorbable dose (MAD) [162], It takes into account the permeability, expressed in terms of a first-order rate constant ka, the solubility cs of the drug, and two physiological variables, the dissolution-intestinal volume V arbitrarily set to 250 ml, and the duration of gastrointestinal absorption ta for 6h ... 

When travelling into space, astronauts are subjected to primary cosmic ray particles, the radiation from solar flares, and also the intense radiation present in the two radiation belts. Savun et al. (1973) have reported measurements in the radiation belts in 1971. Measurements inside a 0.7 g cm" shield indicate that the maximum absorbed dose rate crossing the inner belt was 0.22 Gy h and crossing the outer belt 0.054 Gy h" . 

The basis of this classification system was taken np by the US Food and Drug Administration (FDA) and issned as one of their guidance for industry series of documents. There is one final concept, related to solubility and absorption, that often gives usefnl information on the oral absorption of drug candidates this is the maximum absorbable dose (MAD) (equation (39.1) ... 

QD) dosing regimen could be employed. The effective tm calculated using the AUC accumulation ratio from a 24-h dosing interval is 4h, between the tm,a and li/2ip values, and not the same as the effective tm of 7.5 h calculated from MRTiv. Therefore, which tm controls the duration of a direct response depends on many factors, such as maximum absorbable dose, the timing of the effective concentration, and the frequency of dosing. 

The results of this procedure will give minimum and maximum absorbed doses in the product and on the container surface for a given set of plant parameters, product density and loading pattern. 

Johnson and Swindell (46) proposed a simple predictive model that relates the aqueous solubility and absorption rate constant (K ) to determine the maximum absorbable dose (MAD) ... 

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