Drug-free plasma

FIGU RE 1.38 Chromatograms of LPME-treated drug-free plasma, mirtazapine enantiomers, and mefloquine.156 Chromatograms refer to drug-free plasma (A) plasma spiked with 62.5 ng mL-1 of (+)-(5)-mirtazapine (2) and (-)-(i )-mirtazapine (3) and 500 ng rnL-1 of (R, S)-mefloquine (1,4) (B) plasma sample from a patient treated with 15 mg/day of rac-mirtazapine (C). All samples were pre-treated by LPME. The analysis was performed on a Chiralpak AD column using hexane ethanol (98 2, v/v) plus 0.1% diethylamine at a flow rate of 1.5 mL min-1, A = 292 nm. (+)-(5)-mirtazapine (2), (-)-(f )-mirtazapine (3) and (1, 4) internal standard. (Reproduced with permission from Elsevier.)... 

QC material should be prepared in drug-free plasma containing the same anticoagulant as the samples to be tested. In addition, it is advisable to assess the sensitivity and limit of detection with different matrices using your own LC-MS/MS system. This may differ between matrices and have consequences for the precision and accuracy of detection of the assay. 

Fig. 2.12 Receptor occupancy based on PET scanning and in vitro potency combined with free plasma drug concentration. Log D74 values shown below compound names.

True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cli (intrinsic unbound clearance). 

Increased free fraction in plasma of some highly protein-bound acidic drugs. Free drug clearance of such drugs is better indicator of dose requirements than total clearance Small decreases in free fraction of basic drugs bound to ax-acid glycoprotein... 

E) The free plasma concentration of drug B would likely be markedly increased if drug A were given second rather than first. 

For drugs that bind to serum proteins, equilibrium exists between the bound or ineffective portion and the unbound (free) or effective portion. For acidic drugs that are highly bound to albumin, the free plasma concentration may correlate best with pharmacologic effect. Although albumin levels decrease only slightly with age, they tend to decrease during periods of illness. This can result in elevated levels of... 

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