Absorption maximum absorbable dose

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

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. 

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 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 ... 

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) ... 

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) ... 

Calcium carbonate is the salt of choice because it contains the highest concentration of elemental calcium (40%) and is the least expensive (Table 3-3). It should be ingested with meals to enhance absorption from increased acid secretion. Calcium citrate absorption is acid independent and need not be taken with meals. Because the fraction of calcium absorbed decreases with increasing dose, maximum single doses of600 mg or less of elemental calcium are recommended. 

In another experiment, the irradiated sample was photobleached with IR radiation and then maintained at room temperature in the absence of oxygen until 90% of the radicals had decayed. If the sample was then re-irradiated, the maximum concentration of 4.2 x 1016 electron g 1 was restored after absorption of 3.0x1019 eVg-1. The decrease of the trapped electron concentration was thus assigned by Keyser et al. to a reaction of free radicals with trapped electrons. If the G value for alkyl radicals obtained by Waterman and Dole [214] for linear polyethylene at 77°K is used (G = 3.3), it can be calculated that the concentration of free radicals is 1.5 x 10-3 mole l-1 if the absorbed dose is 3 x 101 9 eV g-1. Scavenging of electrons in hydrocarbon glasses by biphenyl shows that, in this case, 1.5 x 10-3 mole l-1 biphenyl scavenges 50% of the ejected electrons [215]. 

ABSORPTION, EXCRETION, AND DOSING Rosiglitazone (avandia) and pioglitazone (actos) are taken once a day. Both agents are absorbed within about 2 hours maximum clinical effect requires 6-12 weeks. The thiazolidinediones are metaboUzed by the liver and should not be used if there is active hepatic disease or significant elevations of hepatic transaminases. 

The dosimeter containers are usually sealed glass ampoules of 2-5 cm capacities. Fe ion concentration is measured in a spectrophotometer at the absorption maximum of these ions, at 304 nm. The dose is determined from the increase of optical absorbance, AA ... 

Miller et al. (1988) have developed a thin (20 pm) polyvinyl butyral film containing the leucocyanide of pararosaniline, which changes fi om colorless to pink in its useful dose range of 2—100 kGy. The spectrophotometric measurement of the irradiated film is performed at 554 nm at the absorption maximum of the radiation-induced optical band. Another version of the same film contains the same dye and a radiation insensitive additive. Since the optical absorbance measured at 650 nm depends only on the thickness of the film, thus using the difference of the optical absorbance values measured at 554 nm and 650 nm respectively, as response, the measurement of thickness becomes unnecessary. A third version of this type of film is provided with adhesive backing and UV protective cover and it is to be used for reflected light measurement with potential for label dosimetry applications (Kovacs et al. 2000b). 

Capsaicin fed to rats was rapidly absorbed from the stomach, with 85 % of a 3-mg dose absorbed within 3 h [166]. Doses of 5.12 mg/mouse/week led to maximum plasma concentrations of 51.5 ng/mL and 84.8 ng/mL in male and female mice, respectively [167]. Little absorption of capsaicin also occurs across the skin. When 0.8 g of gel containing 0.075 % of capsaicin was applied to the skin of human volunteers, the average absorbed dose after 8 h of exposure was 22.7 pg/cm [168]. Topical application of pure capsaicin to the skin of mice resulted in peak plasma concentrations occurring 4-12 h later, and capsaicin was detectable in the blood 24 h after dosing [167]. 

Measurements of ozone (O3) concentrations in the atmosphere are of particular importance. Ozone absorbs strongly in the ultraviolet region and it is this absorption which protects us from a dangerously high dose of ultraviolet radiation from the sun. The vitally important ozone layer lies in the stratosphere and is typically about 10 km thick with a maximum concentration about 25 km above the surface of the earth. Extreme depletion of ozone in a localised part of the atmosphere creates what is known as an ozone hole. 

Absorption - Following oral administration, amiodarone is slowly and variably absorbed bioavailability is approximately 50%. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose-proportional, with a mean 0.5 mg/L increase for each 100 mg/day. 

Absorption/Distribution - Selegiline is rapidly absorbed approximately 73% of a dose is absorbed maximum plasma concentration occurs 0.5 to 2 hours following administration. 

Fluconazole is well absorbed following oral administration, with a plasma half-life of 30 hours. In view of this long half-life, daily doses of 100 mg are sufficient to treat mucocutaneous candidiasis alternate-day doses are sufficient for dermatophyte infections. The plasma half-life of itraconazole is similar to that of fluconazole, and detectable therapeutic concentrations remain in the stratum corneum for up to 28 days following termination of therapy. Itraconazole is effective for the treatment of onychomycosis in a dosage of 200 mg daily taken with food to ensure maximum absorption for 3 consecutive months. Recent reports of heart failure in patients receiving itraconazole for onychomycosis have resulted in recommendations that it not be given for treatment of onychomycosis in patients with ventricular dysfunction. 

Percutaneous absorption studies using a solution of lindane in acetone have shown that almost 10% of a dose applied to the forearm is absorbed, to be subsequently excreted in the urine over a 5-day period. Serum levels following the application of a commercial lindane lotion reach maximum at 6 hours and decline thereafter with a half-life of 24 hours. After absorption, lindane is concentrated in fatty tissues, including the brain. 

---