Flip-flop kinetics

Flip-flop kinetics is an exception to the usual case in which the absorption rate constant is greater than the elimination rate constant (FCa K). For a drug absorbed by a slow first-order process, such as certain types of sustained-release formulations, the situation may arise where the elimination rate constant is greater than the absorption rate constant (fC fCa). Since the terminal linear slope of plasma drug 

In this simulation, the lower graph (solid line) represents the flip-flop situation. Because of a larger value for the elimination rate constant, the flip-flop graph has both a smaller AUC and a smaller (Cp)max than the normal graph. However, both the regular and flip-flop curves have the same shape and the same tmax (0.305 h). 

When fitting plasma drug concentration data to the one-compartment extravascular model by non-linear regression, estimates for the elimination rate constant and absorption rate constant from regular and flip-flop approaches will have exactly the same correlation coefficient, 

One sure way is to have an rmambiguous value of the drug s elimination half life (and therefore of the elimination rate constant) determined from a study in which the drug is administered intravenously. Another strong indication that the regular model is the correct model is the situation where the extravascular administration is of a type that should not have any kind of slow, extended absorption. An example of this is an immediate release tablet or a capsule. This type of dosage form should not have an absorption half life that is slower than its elimination half life. 

Plot the data and, using the plot, determine the following. 

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The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

Metformin has an absolute oral bioavailability of about 50-60% of the dose after oral application of a single dose. Deconvolution analysis showed that after a short lag-time, the available remainder of the oral dose was absorbed at an exponential rate over about 6 h (Tucker et al., 1981). The bioavailability of phenformin seems to be more variable but also in the range of about 50% (Beckmann, 1968 Travis and Sayers, 1970). In general, absorption of biguanides is slower than their elimination, hence the plasma levels follow flip-flop kinetics (Pentikainen et al., 1979). 

FIGURE 3.8 Schematic description of normal kinetics and flip-flop kinetics. 

Pegaptanib sodium was eliminated from the eye through systemic circulation with a terminal half-life from the vitreous of three to five days in both monkeys and rabbits. The plasma terminal half-life mimicked the vitreous humor half-life, indicative of flip-flop kinetics whereby the rate-limiting step that determines the systemic pegaptanib sodium concentration is the exit of the drug from the eye. From these observations one can estimate the vitreous humor terminal half-life in patients that would approximate the plasma terminal half-life. 

For example, a drug with parameters [1, 0.05, 100] provides an identical concentration-time profile as [0.05, 1,5], Thus, even though ka and ki0 are uniquely identifiable they are indistinguishable in the absence of further information, such as knowledge of what V is. In most situations and without conscious effort, to distinguish between the two outcomes it is assumed that absorption is faster than elimination, ka >> k10, and that Eq. 1.68 is the solution. In case where kio >> ka this is referred to as flip-flop kinetics and Eq. is the solution. Only in the case where both intravenous and extravascular data are obtained can ka and ki0 be uniquely determined (Chan and Gibaldi, 1985). All other cases are based on the assumption of which rate constant is larger, absorption or elimination. 

Is it possible for the rate constant associated with elimination to have a greater value than that for the distribution rate constant The answer to this is "Yes." This type of flip-flop kinetics occurs for the aminoglycoside antibiotic gentamicin. In the case of gentamicin, the terminal (fi) portion of the curve, which represents the slower process, corresponds to distribution while the steep feathered line, whose slope is -a/2.303, corresponds to the faster process (the elimination process in this case). Ordinarily, for most drugs, this is not the case, and we can refer to a as the distribution rate constant and to jS as the postdistribution rate constant. 

When the occurrence of flip-flop kinetics is not recognised it may compromise the interpretation of results from studies on the pharmacokinetic behaviour of slow release dosage forms. Flip-flop pharmacokinetics may occur with any extravascularly administered parenteral slow release dosage form. Intramuscular depot injectimis of antipsychotics such as fluphenazine decanoate, haloperidol decanoate or flupenthixol decanoate show this behaviour. It also occurs after the administration of oral slow release products of active substances such as isoxuptine, carbamazepine, diclofenac, valproic acid, morphine and theophylline. 

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