Drug Absorption and Bioavailability

I will introduce PK/PD and definitions. i will be able to discuss the physics and physiology of absorption, focused totally on oral absorption. i will be able to discuss the biopharmaceutics arrangement , factors affecting oral absorption, then i will be able to discuss kinetics, other extravascular doses, or routes, and that i will land up with bio-equivalents. there's an instant distribution followed by a primary order elimination. The concentration starts at zero and at a particular rate the drug gets absorbed, presents itself to the circulation , reaches a peak, and is then followed by this elimination phase. On the proper hand we see a classical dose response curve where the exposure is expressed as a log value versus the effect followingthe E max model. we need to confine mind that there's not only one dose response, there are really two dose responses. within the green we see here the specified dose response curve for the intended effect, and within the red we see the side effect dose response curve. and therefore the gap in between these two curves is basically the therapeutic window that we are targeting with our therapies. If we now take these two graphs and put them together conceptually, then we see here in green the minimally effective concentration,in red the minimum toxic concentration, and because the drug gets absorbed it crosses the minimum effective concentration and therefore the effect has an onset, it starts. it's a maximum effect, the elimination takes place, and when the concentration drops below the minimum effective concentration, the duration of the effect has ended. And this, again, is that the therapeutic window that we are targeting between the red and green. And if absorption changes within a patient,between patients, we will reach high concentrations leading to toxicity, or lower concentrations leading to lack of efficacy. So, I just want to present some definitions of absorption and bioavailability, what this talk is about. The absorption is that the movement of a drug fromits site of administration into the blood stream, or central compartment, and therefore the extent to which this happens . Bioavailability is defined because the fractional extent that drug reaches it site of action, or the biological fluid. And here you'll already sense that these definitions aren't extremely specific. There's kind of a top quality thereto . it is the bloodstream, the central compartment,the site of action, it isn't very defined. So this bioavailability, this fraction that gets absorbed is basically supported the world under the concentration time profile. then here on the proper we see the world under concentration time profile, the important area under this curve when concentration is plotted linearly. And during this case the areas under both curves are identical then the fraction absorbed is one. On a log scale this leads to these plots with parallel terminal elimination phases. If the fraction is a smaller amount than one, then the oral curve will sink correspondingly and you get a lower exposure. So, in formulas this is often depicted as down here where the world under the concentration time curve after IV dosing is that the dose divided by the clearance. The dose we will determine by choosing the dose, and therefore the clearance may be a biological parameter which will differ between patients. If the dose is given extravascularly, then there's a fraction that gets absorbed, right, this bioavailability, then that then enters the equation. And F are often isolated as here, then you'll determine experimentally this F by ratioing the dose normalized AUC after extravascular administration divided by the dose normalized I -- AUC after IV administration.

Physics and physiology.

Physics and physiology. So, here we see for oral administration the entire path from disintegration of a solid dosing form to individual particles within the gut lumen to dissolution of individual molecules, diffusion towards the gut wall, through the gut wall, getting into the hepatic portal vein then reaching the liver, then finally reaching the circulation . And at any of those steps there's the potential for loss as depicted here. Now absorption is usually considered to require place between the dosing form, and reaching the hepatic portal vein . except for oral bioavailability it also includes this step of getting past the liver. the primary time that every drug molecule has got to make it past the liver. And so, this is often called the primary pass, the primary pass effect. So, just that specialize in a number of these processes individually. And so, drug release are going to be suffering from a spread of things . The excipients that are chosen often fillers,or compounds that aid within the processing of the dosing form. The tablet compression strength is vital for this liquid penetration. And, of course, any coating or matrix that's added to the dosing form to affect these processes. So, if you embed the active pharmaceutical ingredients, the API and polymer matrix that dissolves or swells at a slower rate than the drug, then this may impact the method of liquid penetration. It can also increase the disintegration by swelling up and ending the solid dosing form. additionally , if you coat the tablet you'll create a mass transfer limiting barrier, then you'll create a protracted exposure, an extended release form, otherwise you can make this barrier soluble supported pH. And so, this is often how you'll create enteric coated tablets that don't dissolve within the stomach juice under acidic condition, but do dissolve once the dosing form hits the intestines. The change of the concentration during a solution is hooked in to the diffusion coefficient, the area of your particles, diffusion layer thickness, medium volume, and solubility. And so, if we glance at the baseline curve,the start line , this black line of a base, bases are usually not very soluble then the solubility is extremely low, and also the kinetics are very low. And so, you reach a solubility with a really slow pace. If you now take this same compound ,the base formulated as the bottom , but you decrease the particle size and there by increase the area that's available then you will not get to an equivalent final concentration,but you will get there quicker, and so, this is often the difference between kinetics and dynamics. This increases the solubility so you get to higher total concentrations, and in fact , the speed therefore increases also. Higher solubility you get there quicker also . additionally , you'll also formulate compoundsas an amorphous compound, different polymorphisms, hydrates, anhydrates. and therefore the way you'll believe this is often that if a solid is an amorphous then it isn't during a stable crystal structure, then it requiresless energy for a molecule to go away that solid form and enter the answer , then solubility is enhanced. These different dissolution profiles will then end in different concentration time profiles inside the body, which is depicted here. So, subsequent step is to move these molecules across the enterocyte membrane and enter the biological system, and this is often depicted the various ways in which which will happen. Passive diffusion, trans-cytotic vesicles,we'll not enter that an excessive amount of . Passive diffusion in through the paracellular route with molecules that are hydrophilic and little.