Methadone is an opiate drug that has been identified as an in-vitro substrate of the efflux pump P-glycoprotein (P-gp), active in the intestinal epithelium and in the blood-brain barrier (BBB), among other sites. The objective of this study was to test in vivo, in the rat model, the role of P-gp modulation on the analgesic effect and brain uptake of methadone, as well as identify the most relevant site via dual oral and intravenous (i.v.) experiments. The P-gp specific inhibitor (valspodar or PSC833) was preadministered (10 mg kg(-1) i.v.) to test groups. Analgesia was measured using the tailflick test. The ED50 for oral methadone (2, 3, 6 and 8 mg kg(-1)) decreased three-fold in valspodar groups compared with controls (2.23 +/- 0.002 mg kg(-1) and 6.07 +/- 0.07 mg kg(-1); P < 0.0001). The overall analgesic effect (% antinociception) was elevated 3.1 times in pretreated compared with control rats (90.65% +/- 0.22 vs 29.23% +/- 14.0; P < 0.01) after 6 mg kg(-1) oral methadone and 2.8 times after i.v. (0.35 mg kg(-1)) administration (91.75% +/- 4.27 vs 32.45% +/- 9.0; P < 0.01). The brain:plasma distribution ratio was higher in pretreated animals and AUCbrain (overall brain concentration) was 6 times higher after oral methadone and 4 times higher after i.v. compared with controls, disproportionally increased relative to plasma, implying an active process at the BBB. P-gp, and hence substrate comedication, plays a critical role in the evolution of the methadone analgesic effect and in its brain uptake, independent of the administration route.

For TAC therapy, covariate models using mixed effects methods are most useful when combined with patient-specific biochemical assays as well as clinical evidence. In such cases, the observed C(min) and Bayes methods can provide the most likely individual PK parameters, hence the optimal next dose to reach individualized target levels for each patient.

Because of the indirect nature of the effect exerted by ibuprofen, the implications of differences found in the plasma drug concentration profiles between suspension and effervescent granules are less apparent in the therapeutic response.

Due to the absence of significant changes in the protein binding it is unlikely that there will be an exaggerated pharmacological response in patients with renal and hepatic disease following the administration of a standard propofol dose, although due to interpatient variability careful titration can be recommended.

The effects of in vitro carbamylation of plasma with potassium cyanate on drug-protein binding have been investigated. Potassium cyanate added to samples of normal plasma and incubated for 30 to 150 min induced time-related plasma protein carbamylation. Carbamylation of plasma did not influence quinidine protein binding, but resulted in decreased salicylate binding. The increased free fraction of salicylate in plasma correlated with the degree of carbamylation of plasma proteins (r = 0.99; p less than 0.001). Plasma from patients with chronic renal disease showed varying degrees of plasma protein carbamylation, correlating with the values of free plasma salicylate (r = 0.80; p less than 0.05). Scatchard plots for sulfadiazine binding in plasma from patients with uremia and in normal plasma carbamylated in vitro with potassium cyanate showed changes in the 2 groups when compared with those in normal individuals. If cyanate is produced in vivo from urea in patients with uremia, plasma protein carbamylation may play a role in the decreased plasma protein binding of some acidic drugs.