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- W77833410 abstract "Protein binding can have major impact on a drug’s pharmacokinetics (PK) and pharmacodynamics (PD). At present the theoretical basis of the influence of (alterations in) plasma protein binding on pharmacokinetics is well-established. The role of plasma-protein binding on pharmacodynamics however has sofar not been established in a systematic manner. As such there is no scientific basis for the ‘free drug hypothesis’ which states that the pharmacological activity is correlated with unbound drug concentrations in plasma. The objective of the research described in this thesis is to determine, in a strictly quantitative manner, the influence of plasma protein binding on in vivo pharmacodynamics. To this end both in silico and in vivo investigations were performed using the beta-blockers as model compounds. In contrast to the PK, the free drug concentration is the main determinant of the PD under equilibrium conditions for both target and plasma protein. Moreover for the beta-blockers, the free plasma concentration appears to be the best predictor of in vivo PD. In case of a dynamic interaction, the probability of non-restrictive protein binding is (theoretically) higher with regard to the PD under certain conditions, but more extensive research is needed to confirm this statement." @default.
- W77833410 created "2016-06-24" @default.
- W77833410 creator A5050814135 @default.
- W77833410 creator A5070224582 @default.
- W77833410 date "2008-11-26" @default.
- W77833410 modified "2023-09-27" @default.
- W77833410 title "The 'free drug hypothesis' : fact or fiction?" @default.
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- W77833410 hasPublicationYear "2008" @default.
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