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Review
. 2011 May;2(5):643-72.
doi: 10.4155/tde.11.19.

Flip-flop pharmacokinetics--delivering a reversal of disposition: challenges and opportunities during drug development

Jaime A Yáñez  1 , Connie M Remsberg, Casey L Sayre, M Laird Forrest, Neal M Davies
Affiliations
Review

Flip-flop pharmacokinetics--delivering a reversal of disposition: challenges and opportunities during drug development

Jaime A Yáñez et al. Ther Deliv. 2011 May.

Abstract

Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined.

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Figures

Figure 1
Figure 1. Feathering (the method of residuals) applied to a semi-logarithmic plot of plasma concentration
If the antilogarithmic values of C (solid line) are subtracted from the antilogarithmic values of C′ (dotted line) the negative slope of the natural logarithm of the difference (C′–C, dashed line) is ka; however if kel > ka, flip-flop occurs and the respective slopes of the logarithms of C′ and C′–C are reversed and are ka and kel, respectively. C: Concentration; ka: Rate of absorption; kel: Rate of elimination.
Figure 2
Figure 2. Recombinant HGH mean semilogarithmic plasma concentration–time profiles from dogs
The rate of absorption was calculated by Wagner's modification of the Loo–Riegelman equation [22], while the rate of absorption was multiplied by five to closely approach the plasma concentration profile for easier comparison. Reproduced with permission from [19].
Figure 3
Figure 3. Plasma concentration–time profile following an extravascular dose (oral administration) and an intravascular dose exhibiting flip-flop kinetics exhibiting absorption rate-limited elimination
It can be observed that the terminal portion of the extravascular curve is not parallel with the iv. curve. The latter reflects the true elimination of the drug.
Figure 4
Figure 4. Mean plasma concentrations (± standard deviation, n = 6) of acamprosate after intravenous bolus and oral administration of 9.3 mg/kg
Reproduced with permission from [63].
Figure 5
Figure 5. Serum concentration compared with time profiles for two representative patients after oral administration of 160 mg of furosemide
Each patient was administered furosemide while in the decompensated phase of congestive heart failure (solid lines) and again after attaining dry weight (dashed lines). (A) Patient ten is representative of eight out of 11 patients studied, with a considerable decrease in lag time and time to peak concentration, and a higher peak concentration when the patients achieved dry weight. (B) Patient six is representative of three patients with no changes in pharmacokinetic values between the decompensated and compensated states. Reproduced with permission from [89].
Figure 6
Figure 6. Representative patients with absorption-limited kinetics (A) and decreased renal function (B) in whom terminal phase represents elimination
iv.: Intravenous. Reprinted with permission from [90] © MacMillan Publishers Ltd.
Figure 7
Figure 7. Amoxicillin blood serum concentration versus (A) time after intravenous and intramuscular administration in sheep at 15 mg/kg dose and (B) intravenous and long-acting intramuscular administration in sheep at 15 mg/kg dose
AMX: Amoxicillin; iv.: Intravenous. Reproduced with permission from [110].
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