Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 1: Initial structure-activity relationship studies of a hit from a high throughput screening.

The P2X3 receptor is primarily expressed in the peripheral sensory nerves, and therefore, antagonists of this receptor may be useful for the treatment of chronic pain. Pyrrolinone derivatives have been identified as a novel class of P2X3 receptor antagonists. A lead structure with moderate activity was discovered through a high-throughput screening assay. A structure-activity study led to the discovery of several P2X3 receptor antagonists. Compound 34 showed potent and specific antagonistic activity and analgesic efficacy.

Prediction of human blood-to-plasma drug concentration ratio.

The objective of this study was to predict R(b) (blood/plasma ratio) in humans using a simple method. Human and rat R(b) and free fraction in plasma (f(p)) values were obtained from the literature. The ratio of total red blood cell concentration to the free concentration in plasma (K(b)) was calculated using f(p) and R(b). Four methods were used for the prediction of R(b): (A) use of rat R(b); (B) use of R(b) calculated from rat K(b) and human f(p); (C) correlation of human log ((1-f(p))/f(p)) and human log K(b); and (D) correlation of log D with human log K(b). The R(b) of 96 compounds in humans ranged from 0.52 to 2.00, with an average of 0.89. A significant correlation was observed among human log K(b), human log ((1-f(p))/f(p)), and log D; however, no obvious correlation was observed among human R(b), human log ((1-f(p))/f(p)), and log D. The errors within 1.25-fold for methods A-D were 68.3%, 77.6%, 61.5% and 64.8%, respectively. All predictive methods considered here were superior to the use of the average value of human R(b) or R(b)=1. Rat R(b) corrected by human f(p) improved the accuracy of the prediction. Method B was the most accurate of the four methods.

The pharmacokinetics of ceftriaxone based on population pharmacokinetics and the prediction of efficacy in Japanese adults.

OBJECTIVE: By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration. METHODS: The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained. RESULTS: Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure.

AIMS: The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS: Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS: The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E(max) model with E(max) of -11.7 mmHg and EC(50) of 423 microg l(-1) was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h. CONCLUSIONS: AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.

Pharmacokinetics of oseltamivir in young and very elderly subjects.

BACKGROUND: Pharmacokinetic studies of oseltamivir in very elderly patients (> or = 80 y) have not previously been performed. OBJECTIVE: To compare the pharmacokinetics of oseltamivir and the active carboxylate metabolite in healthy young and very elderly Japanese subjects. METHODS: Young (20-35 y, fasting, n = 7) and very elderly subjects (> or = 80 y, fed, n = 5) were enrolled in single-center studies and received a single oral dose of oseltamivir 75 mg. Plasma and urine samples were collected (24 h) for pharmacokinetic analysis, and safety was assessed. RESULTS: The time to maximum plasma concentration (tmax) for oseltamivir was delayed in the very elderly compared with the young subjects (2.30 vs 0.71 h, respectively). Furthermore, oseltamivir maximum plasma concentration (Cmax) and AUC(inf) were 52% and 80% higher, respectively, in the very elderly compared with the young subjects. Oral clearance was 45% lower in elderly patients, possibly due to the effects of administration of oseltamivir with a meal. For the active metabolite, oseltamivir carboxylate, Cmax and AUC(inf) values were, respectively, 22% and 91% higher in the very elderly subjects than in the young subjects, while oral clearance was 50% lower in the elderly population. The increased exposure of the active metabolite is likely to correlate with an age-related decline in renal function. For both oseltamivir and the active metabolite, there was large interpatient variability in the Cmax values. The data reported here indicate that oseltamivir would be effective in both of these populations, as trough concentrations for the active metabolite at 12 and 24 hours exceeded the 50% inhibitory concentration against the neuraminidase of influenza A and B isolates by more than 50-fold. Oseltamivir was well tolerated in both groups. CONCLUSIONS: Exposures (AUC(inf)) to both the parent drug and active metabolite were increased by more than 80% in the small number of very elderly subjects presented here. However, oseltamivir was well tolerated by these subjects.

Estimation of serum protein binding of compounds metabolized in serum using matrix inhibition.

It is difficult to evaluate the serum protein binding of compounds that are metabolized in rat serum, even when using ultrafiltration. Protein binding was estimated using matrix inhibition, a method that uses the change in metabolic velocity achieved by changing the free fraction of a compound in the incubation mixture by diluting the serum with phosphate buffered saline. The T(1/2) of phenyl nicotinate, benzyl nicotinate, octyl nicotinate, hexyl nicotinate, butyl nicotinate and [(3)H] compound A were 0.165, 0.780, 2.62, 3.94, 5.22 and 135 min, respectively, with protein binding values of 82.1%, 91.6%, 98.8%, 98.5%, 85.5% and 96.9%. The protein binding value of compound A estimated by ultrafiltration was 93.4%, indicating that the two methods give similar values. The matrix inhibition method is thus applicable for the evaluation of compounds metabolized in serum, and provides a simple, useful method to determine protein binding.

New method for the simultaneous estimation of intrinsic hepatic clearance and protein binding by matrix inhibition.

The purpose of this study was to develop a method for estimating the hepatic clearance (CL(h)) without using a protein binding test. This method allows the simultaneous evaluation of the intrinsic hepatic clearance (CL(int)) with a correction for microsomal binding, and the free fraction in the serum (fu). It uses the decrease in metabolic velocity achieved by decreasing the free fraction of a compound in the incubation mixture (fu(inc)) by the addition of serum, and by changing the microsomal protein concentration. This method is denoted as the 'matrix inhibition method', because it uses the inhibition of the metabolic velocity by the incubation matrix. The metabolic rates of eight compounds (diazepam, imipramine, warfarin, and compounds A-E) were evaluated under several incubation conditions using rat serum and microsomes. The correlation of CL(int) evaluated using the method and using equilibrium dialysis after the CL(int) was corrected for microsomal binding was r = 0.968. The correlation of fu . CL(int) was r = 0.996. Although the method required a high enough fu and fu(microsomes) difference among the reaction conditions for each compound, it could evaluate CL(int) and fu simultaneously and easily by adding additional reaction conditions to the metabolic stability tests performed in ADME screening.