A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

Background and purpose:The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. Experimental approach: Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg·kg -1 ·day -1 ; dalcetrapib 100, 300 or 500 mg -1 ·kg·day -1 ; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days' treatment with torcetrapib 40 mg·kg -1 ·day -1 , dalcetrapib 500 mg·kg -1 ·day -1 or vehicle was measured by quantitative polymerase chain reaction. Key results: Torcetrapib transiently increased mean AP in normotensive rats (+3.7 Ϯ 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 Ϯ 0.6 mmHg with 40 mg·kg -1 ·day -1 at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas. Conclusions and implications:In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.

1. Tofogliflozin is a novel and selective SGLT2 inhibitor increasing glucosuria by inhibition of glucose re-absorption in the kidney for the treatment of type 2 diabetes mellitus. 2. In this study, the metabolism and the mass balance of tofogliflozin was evaluated following administration of a single oral dose of 20 mg [(14)C]-tofogliflozin to six healthy subjects. 3. Tofogliflozin underwent mainly oxidative metabolism in the ethylphenyl moiety, but also minor glucuronide conjugates of metabolites and the parent drug were formed. 4. In plasma, the parent drug and its major phenyl acetic acid metabolite M1 accounted for 42% and 52% of the total drug-related material, respectively. The hydroxyl metabolites and their successor ketone metabolite showed an exposure well below 5%, along with an acyl glucuronide of M1. 5. Tofogliflozin was completely absorbed with subsequent predominate metabolic clearance and a small contribution of direct urinary elimination. Approximately, 76% of the dose was excreted in urine and 20% in faeces within 72 h. The high absorption of tofogliflozin was exemplified by the small trace of parent drug in faeces. The phenyl acetic acid metabolite M1 was the major component excreted in urine and faeces accounting for more than half of the dose. Tofogliflozin demonstrated a high metabolic turnover.

No abstract

1 The binding kinetics of diclofenac to hepatocellular structures were evaluated in the perfused rat liver using the multiple indicator dilution technique and a stochastic model of organ transit time density. 2 The single-pass, in situ rat liver preparation was perfused with bu er solution (containing 2% albumin) at 30 ml min 71 . Diclofenac and [ 14 C]-sucrose (extracellular reference) were injected simultaneously as a bolus dose into the portal vein (six experiments in three rats). An analogous series of experiments was performed with [ 14 C]-diclofenac and [ 3 H]-sucrose. 3 The diclofenac out¯ow data were analysed using three models of intracellular distribution kinetics, assuming (1) instantaneous distribution and binding (well-mixed model), (2)`slow' binding at speci®c intracellular sites after instantaneous distribution throughout the cytosol (slow binding model), and (3)`slowing' of cytoplasmic di usion due to instantaneous binding (slow di usion model). Abbreviations: CL BT , membrane permeation clearance; d, relaxation time of the di usional equilibration process; D e , e ective di usion coe cient; F, hepatic availability; f mob , fraction of mobile particles in cytosol; k in , k out , in¯ux and e ux rate constants; k on , k o , binding and unbinding rate constants; MSC, model selection criterion; Q,¯ow rate; RTD, residence time density; SB, slow binding; SD, slow di usion; TTD, transit time density; t, time constant corresponding to rate constant (=1/k); V B , extracellular volume; V C , initial distribution volume of the cellular phase (n c =V C / V B ); V T apparent cellular distribution volume (n=V T /V B ); WM, well-mixed