Exceptions to the Free Drug Principle

Exceptions to the free drug principle refer to situations where the unbound drug levels in a pharmacologically relevant compartment cannot be easily rationalized or target occupancy does not appear to be driven by unbound drug levels. In most such cases, the discrepancies relate to non-steady-state behavior or reflect the action of an energy-driven transport phenomenon. A number of such real or apparent exceptions have been cataloged in a recent review [3]. 

A microdialysis study was carried out to examine transport of oxycodone into the brain of rats [67], Oxycodone was administered by i.v. infusion, and unbound drug concentrations were monitored in both vena jugularis and striatum. Steady-state equilibrium was reached rapidly and drug levels in the two compartments declined in parallel at the end of the infusion. An unbound brain to unbound plasma ratio of 3.0 was measured which is 3- to 10-fold higher than for other opioids, and explains the similar in vivo potency of oxycodone in spite of lower receptor affinity. The authors interpret these data as de facto evidence of the existence of an as-yet unidentified transporter that carries oxycodone across the blood-brain barrier. 

A study of the potency of the antibiotic daptomycin cited plasma protein binding of 92%, but it claimed only a 2-fold shift in potency in serum (expected 12-fold) [68]. This type of discrepancy is relatively common and can often reflect substantial binding to components in the serum-free media. In the cases of HIV-directed non-nucleotide reverse transcriptase inhibitors, this has been dealt with by measuring the unbound drug concentration in the serum-free medium and using that data to calculate the intrinsic, serum-free potency [69]. 

A report on the binding of the anesthetic propofol to human serum albumin and to plasma presents a dataset that challenges simple notions of equilibria [70]. The unbound fraction of propofol was found to increase sharply at low drug concentrations. The authors appear to have carefully eliminated possible artifacts. Explanations based on cooperative binding modes are discussed though no clear explanation emerges. 

Examination of apparent exceptions to the free drug principle is important because such studies can lead to the identification of new processes that may be important for understanding drug action in certain circumstances. 

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