Flip-flop pharmacokinetics

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. 

In the absence of concentration-time profiles after IV administration, it is impossible to estimate the actual elimination rate constant, and the interpretation of absorption and elimination rates after SC administration of macromolecules must be done cautiously. It is for this reason surprising that so few published pharmacokinetic studies include IV administration to assess whether or not the macromolecule follows flip-flop pharmacokinetics. 

Pharmacokinetic Tools to Characterize Absorption Kinetics. The sustained character of lung absorption is important for the degree of pulmonary selectivity. It is therefore important to evaluate lung absorption with pharmacokinetic tools. Several tools have been used to provide this information, including the time to reach the maximum plasma concentration (tmax), the mean absorption time (MAT), flip-flop, and deconvolution. These approaches are described next. 

Benzathine salts have particularly low aqueous solubility and, when injected intramuscularly, form a depot from which dissolution occurs slowly. Indeed, all benzathine benzylpenicillin salts have been banned from use in the food-producing animals in the EU, because of persistence at and erratic rate of depletion from injection sites and a consequent perceived hazard to human health. Procaine salts, on the other hand, are somewhat more water-soluble and remain in widespread use, formulated as aqueous or oily suspensions. These formulations provide flip-flop pharmacokinetics with terminal half-lives in the range of 8.9-17.0 h after intramuscular or subcutaneous dosing to calves and adult cattle. In some studies, absorption... 

The terminal half-life of erythromycin A in calves and adult cows is relatively short (2.9-4.1 h) after intravenous administration, but much longer after intramuscular (11.9 h) or subcutaneous (18.3 to 26.9 h) dosing, as a consequence of flip-flop pharmacokinetics of commercially available formulations, that is, of a very slow process of drug... 

Injection Site Residues and Flip-Flop Pharmacokinetics... 

However, for many AMDs and indeed drugs of other classes (e.g., anthelmintics), there has long been a practice of developing slow-release (depot) formulations, administered intramuscularly, subcutaneously, or as pour-on products, for use in farm animal species. As discussed in Section 2.2.3, these products commonly display flip-flop pharmacokinetics, in which the terminal half-life represents a slow absorption phase and is longer than the elimination half-life determined after intravenous dosing. The advantages and disadvantages of depot preparations are summarized in Table 2.15. 

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. 

Yanez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM (2011) Flip-flop pharmacokinetics - challenges and opportunities during drug development. Ther Deliv 2(5) 643-672... 

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