The process of drug discovery applies rigorous selection pressures. Marketed oral drugs will generally possess favorable physiochemical properties with respect to absorption, metabolism, distribution, and clearance. This paper describes a study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed. The aim is to identify the trends in physiochemical properties that favor a drug's successful passage through clinical development and on to the market. Two libraries were created, one of current development oral drugs and one of marketed oral drugs. Statistical analysis of the two showed that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean molecular weight of marketed oral drugs. It is also clear that the most lipophilic compounds are being discontinued from development.

ABSTRACT:The apparent intrinsic clearance of 13 drugs has been determined using rat liver microsomes at three different concentrations of microsomal protein. The kinetics was studied using the in vitro half-life method. The nonspecific binding of these drugs to the microsomes was also studied under the same conditions, except for cofactor removal, using equilibrium dialysis. The intrinsic clearances are shown to be dependent on the microsomal concentration, but are approximately constant when corrected for the extent of nonspecific binding to the microsomes. The large difference between observed intrinsic clearance and unbound intrinsic clearance that exists for some compounds, particularly lipophilic bases, is highlighted. A simple model has been developed for understanding the binding of compounds to microsomes and is demonstrated to accurately predict the extent of microsomal binding at one concentration of microsomes from measurement at another. The binding of a further 25 drugs to rat liver microsomes at a microsomal concentration of 1 mg/ml was also studied, along with measurements of lipophilicity using octanol-water partition coefficients. It is shown that the extent of microsomal binding is correlated with lipophilicity, but that basic compounds show a different behavior to acidic and neutral compounds. Microsomal binding is shown to be best predicted using a model where logP is used for basic compounds, and logD 7.4 is used for acidic and neutral compounds. This model has been developed further so that the extent of binding to microsomes of any given concentration can be estimated purely from a knowledge of lipophilicity and ionization.In recent years, kinetic measurements using liver microsomes have been increasingly used as a measure of the rate of metabolic drug oxidation in drug discovery. The results from these in vitro assays are then frequently processed, through a variety of methods, to produce predictions of the in vivo metabolic clearance of compounds in humans (Iwatsubu et al., 1997;Obach et al., 1997;Lave et al., 1999). Methods that are often used for scaling such in vitro data to in vivo predictions are the well stirred model and the parallel tube model, and these models contain plasma free fraction terms that account for the effect of plasma binding on the clearance of compounds (Pang and Rowland, 1977). However, it is frequently found that inclusion of the plasma binding correction can lead to underprediction of the in vivo clearance, particularly for nonacidic compounds, and better performance can often be obtained by ignoring the correction altogether (Obach 1997(Obach , 1999Obach et al., 1997). It has been recognized that nonspecific microsomal binding in the in vitro metabolic assays can significantly affect the observed kinetics of metabolism and hamper the accurate prediction of clearance, and there are now several examples where knowledge of the extent of microsomal binding can lead to a better understanding of the relationship between in vitro metabolism and in vivo pharmacokinet...

ABSTRACT:The binding of 17 drugs to rat hepatocytes has been determined using equilibrium dialysis in combination with metabolic inhibitors and a kinetic model for the binding and dialysis processes. Metabolic inhibitors were used to retard the main routes of metabolism such that the half-life for turnover of the drugs was comparable to or greater than the time scale of the equilibrium dialysis process. Further experiments were carried out to determine the kinetics of diffusion of the compounds across the dialysis membrane and the observed extent of binding to hepatocytes. Knowledge of the rate of metabolism of the drugs in the presence of the inhibitors, the kinetics of the dialysis process, and the observed extent of binding was then used with a kinetic model of the system to give true free fractions of the drugs in live hepatocytes. Further studies show that, for this set of compounds, there is no significant difference in the extent of binding to live or dead hepatocytes. The extent of hepatocyte binding is correlated with lipophilicity, and the best model for binding uses log P for basic compounds and log D 7.4 for acidic and neutral compounds. Hepatocyte binding is also demonstrated to be highly correlated with microsome binding.The kinetic data from microsome or hepatocyte intrinsic clearance assays are often used for the prediction of in vivo metabolic clearance through the use of in vitro-in vivo scaling using methods such as the well stirred model and the parallel tube model (Pang and Rowland, 1977). It has been recognized that nonspecific binding in the in vitro metabolic assay medium can significantly affect the observed kinetics of metabolism and hamper the accurate prediction of clearance. Nonspecific binding has been fairly well studied using microsomes, and there are several examples where knowledge of the extent of microsomal binding leads to a better understanding of the relationship between in vitro metabolism and in vivo pharmacokinetics (Lin et al.,

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