Unbound drug

Equation (1) was derived assuming no protein binding, whereas, in fact, CLint should be defined in terms of the maximum ability of the organ to remove unbound drug because only unbound drug can bind to enzymes and excretory molecules. By including the unbound fraction of drug in Eq. (4) one obtains... 

Figure 4 Representation of protein-bound and unbound drug in a noneliminating membrane-limited organ structure. See text for definition of symbols. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

The binding of drugs to plasma proteins has a significant effect on pharmacokinetics and pharmacodynamics. The fraction of unbound drug, also called the... 

A number of recent publications indicate that the antibacterial field has adopted the concept of comparing free drug concentration at the site of action to in vitro drug potency reported as MIC [24-26]. A study of the antibacterial ertapenem in healthy volunteers was carried out to provide support for its use in skin and skin-structure infections [27]. Using microdialysis techniques, unbound drug concentrations in muscle and subcutaneous tissues were sampled at... 

There has been a major advance in our understanding of drug exposure in the CNS as detailed in the seminal paper of Kalvass and Maurer and in follow-up publications (vide supra) [9,12,13]. This work emphasizes the importance of unbound drug in the brain, and its relationship to unbound drug in the plasma and brain/plasma ratio. One expects that this work should have a major impact on how CNS drugs are optimized and evaluated. There appears to be little... 

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 system based on microdialysis coupled with flow-injection chemiluminescence detection allows for direct sampling of unbound drug without extractive sample preparation [72], A similar approach based on continuous ultrafiltration has also been reported [73]. Modifications designed to overcome challenges of low solubility and high-non-specific binding in the ultrafiltration approach have also been described [74]. 

Some dmgs are bound to plasma proteins in blood. Plasma protein levels in blood may be decreased in the elderly, but this is most often not clinically relevant since a drug s elimination increases when the free, unbound drug concentration is enhanced (Turnheim 1998). The plasma albumin level may however be markedly decreased in elderly suffering from malnutrition or severe disease. For those patients the concentration of the free unbound drug can reach toxic levels (Waiter-Sack and Klotz 1996). 

UDP-a-glucuronic acid 90 unbound drug concentration 50 unbound drug 24,125 GABA uptake inhibitors 6 histamine -receptor antagonists uptake of drugs in the brain 6 urea 42 urine 62, 67... 

Apparent volume of distribution of free (unbound) drug Maximum rate of reaction (Michaebs-Menten enzyme kinetics) Dosing interval in terms of half-life (= Tjtip)... 

Measurement of the unbound drug present in the circulation and basing pharmacokinetic estimates on this, allows the in vitro and in vivo data to be rationalized. 

We thus have a series of unbound drug affinity measures relating to the action of the drug. The values are those typically obtained by the pharmacologist and form the basis of the structure-activity relationships which the medicinal chemist will work on. It is possible to extend this model to provide a pharmacokinetic phase as shown in Figure 2.9. 

---