The debate on animal ADME studies in drug development: an update.

The preparation and release of the International Conference on Harmonisation guideline on safety evaluation of human metabolites and the technical progresses in bioanalysis have triggered an intense debate on the value of absorption, distribution, metabolism and excretion radiolabelled studies in animals. Some authors have radically challenged the traditional approach whereas others, while accepting the need of significant changes, argue that these studies remain an irreplaceable component of the preclinical registration dossier. This paper reviews some of the representative positions and describes the potential evolution.

Dogs and monkeys in preclinical drug development: the challenge of reducing and replacing.

Introduction: Animal experimentation is a very contentious issue affecting reputation of drug industry. There are several reasons to forecast an increase in the number of dogs and monkeys used in safety and pharmacokinetic studies. This increase may trigger a strong reaction of the public opinion.

Preclinical in vivo ADME studies in drug development: a critical review.

Introduction: The last two decades have brought many fundamental changes to the drug development process. One such change is the importance of preclinical pharmacokinetics, which has become an essential part of early drug discovery. Furthermore, bioanalytical methods have become more sensitive and the identification and quantitation of metabolites can now be carried out on limited amount of biological material.

Plasma protein binding and blood-free concentrations: which studies are needed to develop a drug?

Introduction: The plasma protein binding of drugs and metabolites is known to influence their pharmacokinetics and, therefore, their effects. Evaluating the extent and the linearity of protein binding is an essential piece of information that has to be generated during drug development. Blood cell partitioning has a similar relevance.

Drug and metabolite concentrations in tissues in relationship to tissue adverse findings: a review.

Introduction: Drug blood (or plasma) levels measured during safety preclinical investigations do not always correlate with toxicological findings. Concentrations in target tissues or, even better, at target receptors would probably be more relevant. In addition, toxicity may be caused by drug metabolites which, in turn, can be tissue specific.

Casopitant: in vitro data and SimCyp simulation to predict in vivo metabolic interactions involving cytochrome P450 3A4.

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S), GW679769] has previously been shown to be a potent and selective antagonist of the human neurokinin-1 receptor, the primary receptor of substance P, both in vitro and in vivo, with good brain penetration properties. On the basis of this mode of action it was evaluated for the prevention of chemotherapy-induced and postoperative nausea and vomiting, and for the chronic treatment of anxiety, depression, insomnia, and overactive bladder. Casopitant is shown to be a substrate, an inhibitor, and an inducer of CYP3A4, and, because of this complex behavior, it was difficult to identify the primary mechanism by which it may give rise to drug-drug interactions (DDIs) of clinical relevance.

Disposition and metabolism of [14C]SB-649868, an orexin 1 and 2 receptor antagonist, in humans.

N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [(14)C]SB-649868 was determined in eight healthy male subjects using an open-label study design after a single oral dose of 30 mg. Blood, urine, and feces were collected at frequent intervals after dosing, and samples were analyzed by high-performance liquid chromatography-mass spectrometry coupled with off-line radiodetection for metabolite profiling and characterization.

Tissue distribution and characterization of drug-related material in rats and dogs after repeated oral administration of casopitant.

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)] has been shown to be a potent and selective antagonist of the human neurokinin 1 receptor, the primary receptor for substance P. During long-term toxicity studies conducted in rat and dog, evidence of cardiomyopathy and increased cardiac weight were observed. The distribution and metabolism of casopitant were studied in both species evaluating the accumulation of drug-related material (DRM) after repeat dosing and its potential relationship with pathological findings observed in myocardium.

Metabolic disposition of casopitant, a potent neurokinin-1 receptor antagonist, in mice, rats, and dogs.

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)] is a potent and selective antagonist of the neurokinin-1 (NK1) receptor, developed for the prevention of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. Absorption, distribution, metabolism, and elimination of [(14)C]casopitant have been investigated in the mouse, rat, and dog after single oral administration and compared with those in humans. [(14)C]Casopitant was rapidly absorbed in all three species: the maximum plasma concentration of radioactivity was generally observed 0.

Expression and distribution of CYP3A genes, CYP2B22, and MDR1, MRP1, MRP2, LRP efflux transporters in brain of control and rifampicin-treated pigs.

The in vivo effect of rifampicin, a potent ligand of PXR, on gene expression of CYP2B22, 3A22, 3A29, 3A46, CAR, PXR and MDR1, MRP1, MRP2, LRP transporters in liver and cortex, cerebellum, midbrain, hippocampus, meninges and brain capillaries of pig was investigated. Animals were treated i.p.

Disposition and metabolism of radiolabeled casopitant in humans.

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)-(GW679769)] is a novel neurokinin-1 receptor antagonist being developed for the prevention of chemotherapy-induced and postoperative nausea and vomiting. The disposition of [(14)C]casopitant was determined in a single-sequence study in six healthy male subjects after single-dose 90-mg i.v.