These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

The transdermal absorption of a series of nonsteroidal antiinflammatory drugs (NSAIDs): indomethacin, ketoprofen, diclofenac, piroxicam, tenoxicam, ketorolac, and aceclofenac) was studied in vitro with human skin. The purpose of the study was to determine the permeation parameters (permeability rate constant, Kp; lag time, TL, and flux, J) as measures of the intrinsic transdermal permeabilities of these drugs to predict their potential for formulation in a transdermal therapeutic system (TTS). A linear correlation was established between the intrinsic log Kp values and the intrinsic partition coefficients (r = 0.863, p = 0.012, n = 7). Diclofenac had the highest value of in vitro transdermal penetration at approximately 0% ionization (Kp = 3.5 cm/h) and ketoprofen had the highest flux (J = 16 micrograms/h.cm2) of the NSAIDs assayed. Ketorolac would provide the plasma concentrations at steady state that would be nearest to the therapeutic concentration (Cr/Css = 26). Also, considering the whole permeation profile in vitro, ketorolac would be the most suitable candidate of the series studied to be formulated as a TTS.

No abstract

The objectives of the current work were to develop a predictive population pharmacokinetic (PK)/pharmacodynamic (PD) model for the testosterone (TST) effects of triptorelin (TRP) administered in sustained-release (SR) formulations to patients with prostate cancer and determine the minimal required triptorelin serum concentration (C TRP_min ) to keep the testosterone levels of the patients below or equal to the level of castration (TST Յ0.5 ng/ml). A total of eight healthy male volunteers and 74 patients with prostate cancer received one or two doses of triptorelin injected subcutaneously or intramuscularly. Five different triptorelin formulations were tested. Pharmacokinetic (serum concentration of triptorelin) and pharmacodynamic (TST levels in serum) data were analyzed by using the population approach with NONMEM software (http://www.iconplc. com/technology/products/nonmem/). The PK/PD model was constructed by assembling the agonist nature of triptorelin with the competitive reversible receptor binding interaction with the endogenous agonist, a process responsible for the initial and transient TST flare-up, and triggering down-regulation mechanisms described as a decrease in receptor synthesis. The typical population values of K D , the receptor equilibrium dissociation constant of triptorelin, and C TRP_min to keep 95% of the patients castrated were 0.931 and 0.0609 ng/ml, respectively. The semimechanistic nature of the model renders the predictions of the effect of triptorelin on TST possible regardless the type of SR formulation administered, while exploring different designs during the development of new delivery systems.