Elimination half life parameters affecting

It is important to note that the elimination half-life is a derived term, and any process that changes k will change the half-life of the drug. Factors that may affect pharmacokinetic parameters are discussed elsewhere, but in this example may include disease states, changes in urinary pH, changes in plasma protein binding, and coadministration of other drugs. 

Diltiazem was shown to exhibit dose dependent (30 mg - 120 mg administrated orally, three times a day) nonlinear pharmacokinetics (43) when administered to healthy individuals. The nonlinearity of diltiazem area under the curve (AUC) is a result of dose dependent first pass metabolism and is not reflected in the elimination half-life which is the same regardless of dose. The mean apparent oral clearance (44) and half-life of diltiazem following chronic oral therapy was 20.9 mL/min/kg and 3.5 hours, respectively. After a constant rate infusion, diltiazem was also shown to exhibit (45) nonlinear pharmacokinetics. After IV administration the following pharmacokinetic parameters were determined in healthy male volunteers the elimination t-1/2 (40) was 11.2 hours and the total clearance was 11.5 mL/min/kg. Diltiazem elimination is affected by liver damage (46) but not by kidney failure. 

A lower creatinine clearance value will affect other so-called "constant" parameters such as the elimination and/or excretion rate constants (K or jy, the elimination half life (ti/2) and, possibly, the apparent volume of distribution. These, in turn, will influence the value of any other pharmacokinetic parameter mathematically related to them. (This example is for a one-compartment model). These parameters include plasma concentration (Cp) at any time t, the area under the concentration versus time curve from t— 0 to t= °°, and clearance. 

Further support for the thesis that the observed drug-membrane interaction directly or indirectly affects the receptor and does not represent pharmacokinetic influences can be derived from preliminary data of a small set of five derivatives for which some pharmacokinetic parameters were determined in rats [41]. The pharmacokinetic parameters - area under the curve (AUC), elimination rate constant (kd ), half-life (to 5), the time of maximal concentration (tmax), and maximal concentration (cmax) - did not correlate significantly with either log 1/ED50(MES), log Al/T2, or log fC0i t. Instead, even for this small set of compounds, log 1 /ED50(MES) correlated again significantly with both parameters log Al/T2 and log K ocL (r = 0.998 and 0.973 respectively). 

The use of half-life incorporates the variables that can influence the rate of drug elimination, those that affect distribution and clearance, whereas the use of systemic clearance focuses on the process of elimination, and corrections can be made for the extent of binding to plasma proteins and for estimated maximum life-span potential. Corrections seem to be justifiable when the human is included in the interspecies scaling technique. The necessity to apply correction factors, however, detracts from the use of allometric scaling for predicting the values of pharmacokinetic parameters. 

These relationships assist in describing how these various parameters affect each other. For example, it can be seen that a reduction in clearance leads to a slower elimination and therefore a longer half life. Similarly, an increase in volume of distribution (increased tissue binding and sequestration of drugs away from the central... 

Half-life has little value as an indicator of the processes involved in either drug elimination or distribution. Yet, early studies of drug pharmacokinetics in disease states have relied on drug half-life as the sole measure of alteration in drug disposition. Disease states can affect the physiologically related parameters, volume of distribution and clearance thus, the derived parameter, half-life, will not necessarily reflect the expected change in drug elimination. 

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