Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model.

Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15.

Pharmacokinetics and bioavailability of a metformin/glyburide tablet administered alone and with food.

Two randomized crossover studies were conducted to evaluate the pharmacokinetics (including food effect) of fixed-combination metformin/glyburide tablets. Pharmacokinetics and bioavailability of two strengths (500 mg/2.5 mg and 500 mg/5 mg) of metformin/glyburide tablets were assessed relative to coadministered metformin and glyburide tablets in study 1.

Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.

Aims: The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects.

Methods: An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v.

Toxicokinetics of 2',3'-didehydro-3'-deoxythymidine, stavudine (D4T).

The toxicokinetic profile of D4T was assessed by conducting in vivo and in vitro studies. In the various studies, the i.v.

In vivo evaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy.

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit.

Evaluation of the effect of food on the pharmacokinetics of avitriptan.

Bioavailability of avitriptan was found to decrease significantly when administered 5 min after a standard high fat meal. The studies described herein were carried out to gain insight into the mechanism of this food effect. A series of studies were conducted in humans to assess the effect of timing of meal, type of meal, gastric pH, change in the formulation and dose on the bioavailability of avitriptan.

Oral bioavailability and disposition characteristics of irbesartan, an angiotensin antagonist, in healthy volunteers.

Absolute oral bioavailability and disposition characteristics of irbesartan, an angiotensin II receptor antagonist, were investigated in 18 healthy young male volunteers. Subjects received [14C] irbesartan as a 30-minute intravenous infusion (50 mg), [14C] irbesartan orally as a solution (50 mg or 150 mg), or irbesartan capsule (50 mg). Irbesartan was rapidly and almost completely absorbed after oral administration, and exhibited a mean absolute oral bioavailability of 60% to 80%.

Biotransformation of irbesartan in man.

The metabolism of irbesartan, a highly selective and potent nonpeptide angiotensin II receptor antagonist, has been investigated in humans. An aliquot of pooled urine from healthy subjects given a 50-mg oral dose of [14C]irbesartan was added as a tracer to urine from healthy subjects that received multiple, 900-mg nonradiolabeled doses of irbesartan. Urinary metabolites were isolated, and structures were elucidated by mass spectroscopy, proton NMR, and high-performance liquid chromatography (HPLC) retention times.

Lack of effect of food on the oral bioavailability of irbesartan in healthy male volunteers.

This study was conducted to evaluate the effects of a high-fat meal on the oral bioavailability of an 300-mg irbesartan tablet in healthy male volunteers. Sixteen healthy young male volunteers participated in this single-center, open-label, single-dose, crossover study. Each volunteer received a single 300-mg irbesartan tablet under fasted conditions and 5 minutes after a high-fat breakfast, with administrations separated by a 7-day washout period.

Pharmacokinetic assessment of the sites of first-pass metabolism of BMS-181101, an antidepressant agent, in rats.

The relative contribution of the gut and the liver to the first-pass metabolism of BMS-181101 (3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-fluoro-1H-ind ole dihydrochloride), a potential antidepressant agent, has been evaluated in rats. Nine male Sprague-Dawley rats were divided into three groups of three and each rat received a single 20 mg kg(-1) dose of [14C]BMS-181101 via a 30 min constant-rate intravenous infusion, a 30-min constant-rate intraportal infusion or oral gavage. Serial blood samples were collected for 8 h after dosing and plasma was analysed for unchanged BMS-181101 and total radioactivity.

Assessment of effect of food, gender, and intra-subject variability in the pharmacokinetics of avitriptan.

The objectives of this study were to assess the effect of food and gender on the pharmacokinetics of avitripan. A group of 12 healthy men and 12 healthy women was administered a single 50 mg dose of avitriptan capsule under fasting conditions and 5 min after a high-fat breakfast. The two treatments were repeated in a replicate design to assess the intra-subject variability in the pharmacokinetics of avitriptan under fasted and fed conditions.

A pharmacokinetic interaction study of avitriptan and propranolol.

Objective: To assess whether a clinically significant change in the pharmacokinetics of avitriptan and propranolol is observed in healthy subjects after coadministration of the two drugs.

Methods: The pharmacokinetics of avitriptan and propranolol were investigated when the two drugs administered separately and when two 150 mg doses of avitriptan 2 hours apart were added to a steady-state regimen (80 mg twice a day) of propranolol. The pharmacokinetics of metabolites of avitriptan (N-desmethylavitriptan, methoxypyrimidinyl piperazine, and O-desmethylavitriptan) and the pharmacokinetics of 4-hydroxypropranolol were also assessed.

Pharmacokinetic interaction between butorphanol nasal spray and oral metoclopramide in healthy women.

The pharmacokinetics of butorphanol nasal spray, with and without the coadministration of metoclopramide, were studied in 24 healthy women. In this crossover study all volunteers received 3 treatments: a single, 1-mg dose of butorphanol nasal spray, a single, 10-mg oral dose of metoclopramide, and a combination of a single, 1-mg dose of butorphanol nasal spray and a single, 10-mg oral dose of metoclopramide. There was at least a one-week washout period between sessions.

The effects of age and gender on the single dose pharmacokinetics of avitriptan administered to healthy volunteers.

The effects of age and gender on the single dose pharmacokinetics of avitriptan and its three metabolites were assessed in 15 young men, 15 young women, 15 elderly men and 15 elderly women. Avitriptan was administered as a 150-mg capsule after a 10-hour fast and serial plasma and urine samples were collected up to 36 hours after the dose. Plasma samples were analyzed for avitriptan and its metabolites, N-desmethyl avitriptan (ND048), O-desmethyl avitriptan (OD048), and methoxypyrimidinyl piperazine (MPP).

Effects of age, gender, and diurnal variation on the steady-state pharmacokinetics of BMS-181101, an antidepressant, in healthy subjects.

Objectives: To investigate the effects of age, gender, and diurnal variation on the safety, tolerability, and steady-state pharmacokinetics of BMS-181101, an antidepressant, in humans.

Methods: This was a multiple-dose parallel-design study in 51 healthy subjects (12 young and 12 elderly men and 12 young and 15 elderly women). Each subject received a 15 mg oral dose of BMS-181101 every 12 hours on days 1 through 6 and one dose on day 7.

Clinical pharmacokinetics of nefazodone.

Nefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration.

Lack of effect of food on the steady state pharmacokinetics of BMS-181101, an antidepressant, in healthy subjects.

The effect of food on the pharmacokinetics of BMS-181101, a new anti-depressant under development, was investigated in 12 healthy male volunteers at steady state. Each subject received a 15 mg oral dose of BMS-181101 twice a day (q 12 h) for 11 days and a morning dose of BMS-181101 on day 12. Six subjects were randomly assigned to receive BMS-181101 under fasted conditions from days 1 to 6 and then crossed over to fed conditions from days 7 to 12.

Assessment of dose proportionality, absolute bioavailability, and immunogenicity response of CTLA4Ig (BMS-188667), a novel immunosuppressive agent, following subcutaneous and intravenous administration to rats.

Purpose: The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig.

Methods: A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13.

Microdialysis studies of the distribution of stavudine into the central nervous system in the freely-moving rat.

Purpose: To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS.

Methods: Microdialysis with on-line HPLC analysis was used to measure drug concentrations in the brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) in the freely-moving rat. The in vivo recovery of d4T and zidovudine (AZT) was estimated by retrodialysis, which was validated by the zero-net flux method.

Disposition of [14C]avitriptan in rats and humans.

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans.

The pharmacokinetics of butorphanol and its metabolites at steady state following nasal administration in humans.

The single-dose and steady state pharmacokinetics of butorphanol and its metabolites, hydroxybutorphanol (HO-B) and norbutorphanol (NOR-B), were studied in nine healthy male volunteers. Each subject received a single 1 mg dose of butorphanol on days 1 and 6, and a 1 mg dose every 6 h (q6h) on days 2-5, via nasal administration. Serial blood and urine samples were collected for 24 h after the first dose on day 1 and for 72 h at steady state on day 6.

A multiple-dose pharmacokinetic interaction study between didanosine (Videx) and ciprofloxacin (Cipro) in male subjects seropositive for HIV but asymptomatic.

The pharmacokinetics of didanosine and ciprofloxacin were evaluated following the administration of multiple oral doses of each drug as a single agent or in combination. Didanosine was dosed as the Videx chewable/dispersible tablet, which contains the antacids dihydroxyaluminum sodium carbonate and magnesium hydroxide. Sixteen HIV-seropositive male subjects were randomly assigned to two groups of eight each.

Effects of gender, age, and race on the pharmacokinetics of etoposide after intravenous administration of etoposide phosphate in cancer patients.

The influence of gender, age, and race on the pharmacokinetics of etoposide and on the extent of conversion of etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) to etoposide are summarized. Included in the integrated statistical analyses were 192 patients from six phase I/II studies (102 men and 90 women, 128 aged < or = 65 years and 64 aged > 65 years; 134 were white, 18 were other races, and race was not recorded for 40). The dose of etoposide phosphate ranged from 25 to 200 mg/m2 of etoposide equivalents and was administered as 5-(bolus) to 210-minute intravenous infusions.