Drug rate constants

The first-order rate constant for the decomposition of a certain drug at 25°C is 0.215 month1. 

After intravenous drug administration, a log-convex concentration decline points to a multi-exponential function. For the most frequent case, a bi-exponential equation with the inter-compartment rate constants (k 2) and (k21) can be fitted. 

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). 

DHP drugs bind allosterically. The open L-channel is somehat more permeable to the Ba ion than to the Ca ion but is very much less permeable to the Na ion. Nonetheless, because Na ion concentrations are so much higher than Ca ion concentrations, the actual fraction of charge carried by the two ions is not always so clear. There are a number of states that the L-channel can be in, aside from simply being open or closed. It is the distribution of L-channel molecules among the various states that is influenced by transmembrane voltage. From another view the rate constants between the states are functions of the transmembrane voltage. 

The primary characteristic of a sequential blocker, as observed with the patch clamp technique, is that the reciprocal of the mean duration of the lifetime equals the normal channel closing rate plus the rate constant of channel blockade times the drug concentration. Therefore, increasing the drug concentration shortens the mean channel open time. 

In the treatment of chronic diseases, a long term zero order release dosage form is highly desirable as it reduces fluctuations of drug levels, reduces toxicity and increases patient compliance. Problems in the treatment of both hypertension, a lifetime disorder, and opiate addiction are associated with compliance. The goal of this research is to develop a subcutaneously injectable system which can release drug at constant rates over a long period of time. 

Db = drug in the body De = eliminated drug ka = first-order absorption rate constant kei = overall elimination rate constant... 

Thus after 6 hours the semilog plot of Cp versus time shown in Fig. 10 becomes a straight line and kei can be determined from the slope. Therefore, the overall elimination rate constant for a drug may be accurately determined from the tail of a semilog plot of plasma concentration versus time following extravascular administration if ka is at least five times larger than kei. 

A is a function of the two rate constants (ka and kei), the apparent volume of distribution (Vd), and the amount of drug absorbed (Dg). After ka and kei have been evaluated and A has been determined by extrapolation, a value for Vd can be calculated if it is assumed that Dg is equal to the dose administered, i.e., absorption is 100% complete. 

Example. A tablet containing 100 mg of a drug was administered to a healthy volunteer and the plasma concentration (Cp) versus time data shown in Table 6 were obtained. Figure 11 shows a semi-log plot of these Cp versus time data. The half-life for elimination of the drug can be estimated from the straight line tail of the plot to be 4.7 hours. The overall elimination rate constant is then... 

Often it is unnecessary to calculate an exact value for an absorption rate constant. For example, when several oral tablets containing the same drug substance are all found to be completely absorbed, it may be sufficient to merely determine if the absorption rates are similar to conclude that the products would be therapeutically equivalent. In another instance, it would be possible to choose between an elixir and a sustained-release tablet for a specific therapeutic need without assigning accurate numbers to the absorption rate constant for the two dosage forms. 

If the concentration of the active drug, A, can be monitored, the composite rate constant, k = k + k2 + ky, can easily be determined from the relationship [A] = [A]0e fe where [A]0 is the initial concentration and [A] is the concentration at time t. If the concentrations of A cannot be determined because of assay difficulties, it is still possible to determine k by monitoring one of the degradation products. For example, if the concentrations of B can be assayed as a function of time, and the concentration of B at time infinity, [B], is also determined, the following relationships can be derived ... 

In many drug solutions, it is necessary to use buffer salts in order to maintain the formulation at the optimum pH. These buffer salts can affect the rate of drug degradation in a number of ways. First, a primary salt effect results because of the effect salts have on the activity coefficient of the reactants. At relatively low ionic strengths, the rate constant, k, is related to the ionic strength, p, according to... 

Buffer salts also can exert a secondary salt effect on drug stability. From Table 5 and Fig. 5 it is clear that the rate constant for an ionizable drug is dependent on its pKa. Increasing salt concentrations, particularly from polyelectrolytes such as citrate and phosphate, can substantially affect the magnitude of the pKa, causing a change in the rate constant. (For a review of salt effects, containing many examples from the pharmaceutical literature see Ref. 116.)... 

In a typical research and development setting, in the event that a new drug candidate is recognized by the drug-discovery group, then the dissolution rate constant K for that compound under specified hydro-dynamic conditions can be determined from powder dissolution data and practical size analysis by microscopy. 

Other applications of the previously described optimization techniques are beginning to appear regularly in the pharmaceutical literature. A literature search in Chemical Abstracts on process optimization in pharmaceuticals yielded 17 articles in the 1990-1993 time-frame. An additional 18 articles were found between 1985 and 1990 for the same narrow subject. This simple literature search indicates a resurgence in the use of optimization techniques in the pharmaceutical industry. In addition, these same techniques have been applied not only to the physical properties of a tablet formulation, but also to the biological properties and the in-vivo performance of the product [30,31]. In addition to the usual tablet properties the authors studied the following pharmacokinetic parameters (a) time of the peak plasma concentration, (b) lag time, (c) absorption rate constant, and (d) elimination rate constant. The graphs in Fig. 15 show that for the drug hydrochlorothiazide, the time of the plasma peak and the absorption rate constant could, indeed, be... 

These ideas appear to merit careful consideration. Similarly, the use of nomograms to evaluate the intrinsic absorption rate constants for drugs that may be formulated into oral prolonged-release products may be of value [5],... 

The microscopic rate constants for association and dissociation at a site within an electric field (for block by charged drugs) are exponential functions of the membrane voltage ... 

Xu Xj = amount of drug in compartment 1 and j, respectively ky, kjt = first-order transfer rate constants from compartment 1 to j and from compartment j to 1, respectively Fi0, kj0 = first-order exit rate constants from compartment 1 and j, respectively... 

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