Absorption rate constant Ka

After oral dosing, the bi-exponential Bateman function holds true with the absorption rate constant (Ka). 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

The most common extravascular route is oral. When a solution or a rapidly dissolving solid dosage form is given orally, the absorption process often obeys first-order kinetics. In these cases, absorption can be characterized by evaluating the absorption rate constant, ka, using plasma concentration versus time data. 

The absorption rate constant Ka can be estimated from the effective permeability ... 

Another compartmental transit and absorption model, the GITA model, has been described by Sawamoto et al. [44] and reviewed by Kimura and Higaki [30], In this model the GI tract is divided into eight different well-stirred compartments and similarly to the CAT model presented by Yu et al. ([60], [63]), the transit of drug is described by a first-order transit rate constant (Ki for the intestine and Ks for the stomach). The absorption in each segment is assumed to be a first-order process described by an absorption rate constant (Ka). The amounts of compound in the different compartments are described by Eq. 18 for the stomach (Xs) and Eq. 19 for the intestinal compartments (Xi + i) [44],... 

The rate of appearance of drug in the plasma Cp is directly proportional to the concentration of drug at the site of absorption (C slte 0f absorption)- Like all first-order rate constants, the units of the absorption rate constant ka are 1/time. A plot of drug amount versus time is shown in Fig. 1.7. 

The drawbacks of SC and IM injections include potentially decreased bioavailability that is secondary to variables such as local blood flow, injection trauma, protein degradation at the site of injection, and limitations of uptake into the systemic circulation related to effective capillary pore size and diffusion. The bioavailability of numerous peptides and proteins is, for example, markedly reduced after SC or IM administration compared to their IV administration. The pharmacokine-tically derived apparent absorption rate constant is thus the combination of absorption into the systemic circulation and presystemic degradation at the absorption site. The true absorption rate constant ka can then be calculated as ... 

Bioavailability F (units dimensionless). This is the fraction of drug that appears in a second accessible pool following administration in a first accessible pool. Absorption rate constant ka (units 1/time). This is the fraction of drug that appears per unit time in a second accessible pool following administration in a first accessible pool. 

Figure 11 Effect of varying absorption rate constant (ka) on the concentration time plots for two hypothetical drugs with similar dose, bioavailability, clearance, and volume of distribution. Case 1 (smooth line) ka > ke and Case 2 (broken line) ka < ke (flip-flop situation).

Mahmood 1. Estimation of Absorption Rate Constant (Ka) following Oral Administration by Wagner-Nelson, Loo-Riegelman, and Statistical Moments in the Presence of a Second Peak. Drug Metab Drug Interact 2004 20 85—100. 

Oral drug absorption is often described as a first-order mechanism, and through compartmental modeling, oral absorption is represented by the first-order absorption rate constant, ka (per time unit). Although it is not used in the current example, inclusion of lag time may be needed to better describe absorption processes. The kinetics of drug amount in the plasma following a first-order absorption process is described by a system of differential equations, as follows ... 

A new molecular entity exhibiting one-compartment pharmacokinetics with first-order absorption was assumed. The typical (mean) values of the population PK parameters for the NME were 1 h 17.5L/h, and SOL for absorption rate constant (Ka), apparent clearance (CLIP), and apparent volume of distribution (V/F), respectively. An intersubject variability of 45% (coefficient of variation) was assumed for each of these parameters, and this was assumed to be lognormally distributed with a mean of zero. A proportional error model was assumed for the residual error of 15%. 

When an extravascular dose is given, one-compartment-model serum concentrations rise during absorption, reach Cniax, and then decrease in a straight line with a slope equal to -k/2.303. The equation that describes the data is C = (FDka)/[VD( a -where F is the fraction of the dose absorbed into the systemic circulation. The absorption rate constant (ka) is obtained using the method of residuals. 

Figure 3.13 Model parameter estimates as a function of the prior standard deviation for clearance. A 1-compartment model with absorption was fit to the data in Table 3.5 using a proportional error model and the SAAM II software system. Starting values were 5000 mL/h, 110 L, and 1.0 per hour for clearance (CL), volume of distribution (Vd), and absorption rate constant (ka), respectively. The Bayesian prior mean for clearance was fixed at 4500 mL/h while the standard deviation was systematically varied. The error bars represent the standard error of the parameter estimate. The open symbols are the parameter estimates when prior information is not included in the model.

Each of the exponential decay terms in the generalized multicompartment models represent a distinct phase or change in shape of the plasma concentration versus time curve. The extra (n+l) exponential term for first-order absorption always has the absorption rate constant (ka) in the exponent, and always represents an absorption phase. The exponential term with the smallest rate constant (A ) always represents the elimination phase, and this rate constant always represents the elimination rate constant and always equals the terminal line slope m= — A J. All other exponential terms represent distinct distribution phases caused by the different rates of distribution to different tissue compartments. 

---