A study of the pharmacokinetic interaction of istradefylline, a novel therapeutic for Parkinson's disease, and atorvastatin.

The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n=16) or placebo (n=4) daily for 14 days.

The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects.

Daptomycin pharmacokinetics were studied in adult volunteers who were moderately obese (body mass index [BMI] = 25-39.9 kg/m2) or morbidly obese (BMI > or =40 kg/m2) and a matched (gender, age, renal function) nonobese (BMI between 18.5 and 24.

Population pharmacokinetics of daptomycin.

Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time.

Moderate liver impairment has no influence on daptomycin pharmacokinetics.

Daptomycin (N-decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine-lactone) is a novel cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus. Daptomycin was recently approved for the treatment of complicated skin and skin structure infections caused by aerobic gram-positive bacteria, including those caused by methicillin-resistant and methicillin-susceptible Staphylococcus aureus. This single-dose, parallel-design, matched-controlled study was designed to evaluate the pharmacokinetics of daptomycin in subjects between ages 18 and 80 years with moderately impaired hepatic function (Child-Pugh Class B, n = 10).

Single-dose pharmacokinetics of daptomycin in young and geriatric volunteers.

Daptomycin is a novel lipoprotein antibiotic that was recently approved for the treatment of complicated skin and skin structure infections caused by aerobic gram-positive bacteria. The pharmacokinetics of daptomycin was evaluated after a single 0.5-hour intravenous infusion of 4 mg/kg to groups of young adult (18-30 years) and geriatric (>or= 75 years) volunteers.

Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects.

The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling.

Pharmacokinetics and inflammatory fluid penetration of intravenous daptomycin in volunteers.

The lipopeptide antimicrobial daptomycin was administered intravenously at a dose of 4 mg/kg of body weight to seven healthy male volunteers. The concentrations of daptomycin in plasma, cantharidin-induced inflammatory fluid, and urine were measured by a microbiological assay. The mean +/- standard deviation peak concentrations in plasma and inflammatory fluid were 77.

The disposition (ADME) of antisense oligonucleotides.

Antisense oligonucleotides hold great promise as novel therapeutic agents designed to specifically and selectively inhibit the production of various disease-related gene products. For efficacy to occur, the therapeutic entity must reach the site of action in amounts sufficient to produce the desired therapeutic effect. Pharmacokinetics is defined as the study of the time course of the absorption, distribution, metabolism and elimination (ADME) of drugs.

Disposition and toxicity of a mixed backbone antisense oligonucleotide, targeted against human cytomegalovirus, after intravitreal injection of escalating single doses in the rabbit.

The ocular disposition and toxicity of GEM132, a mixed backbone phosphorothioate oligonucleotide developed for the treatment of cytomegalovirus-induced retinitis, were studied in rabbits for 6 months following single intravitreal injection of 5, 20, or 100 microgram/eye (toxicity) and 3.7, 15.7, or 78.

Oligonucleotide transport in rat and human intestine ussing chamber models.

Cellular and intestinal absorption of naked oligonucleotides (ONs) is limited and still remains a developmental challenge. A previous report in the literature suggests that ON absorption occurs via a paracellular mechanism. The aim of this study was to test this hypothesis using rat and human intestine in a Ussing chamber and in Caco-2 cells.

A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors.

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors.

Pharmacokinetics and tolerability of intravenous trecovirsen (GEM 91), an antisense phosphorothioate oligonucleotide, in HIV-positive subjects.

Trecovirsen, a 25-mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV-positive volunteers as an i.v. infusion.

On the antipyrine test in laboratory animals. Studies in the dog and monkey.

The antipyrine (AP) test has been challenged in species other than humans on the grounds that, in some nonhuman species, particularly on induction, hepatic blood flow may become as prominent a factor in AP clearance as hepatic metabolism. Therefore, we investigated in dogs and monkeys the disposition of AP to determine how well AP serves as a model drug to indicate changes in rates of hepatic clearance. After administration of an oral solution of AP (5 mg/kg) to control dogs, the percentage of the dose absorbed was 98%, based on urinary and fecal excretion of AP and its metabolites.

Pregnancy-specific changes of antipyrine pharmacokinetics correlate inversely with changes of estradiol/progesterone plasma concentration ratios.

Antipyrine pharmacokinetics as well as estradiol and progesterone concentrations were measured in plasma of 11 healthy pregnant women during the first two trimesters and again in the same patients 6 to 20 weeks after interruption of pregnancy. During pregnancy, the clearance of antipyrine increased and its half-life decreased in all but two instances. A significant inverse relationship was found between the degree of pregnancy-specific changes of plasma clearance of antipyrine and estradiol-progesterone plasma concentration ratios: high estradiol-progesterone ratios during pregnancy corresponded to decreased plasma clearance of antipyrine; low ratios of the two hormones during pregnancy corresponded to increased plasma clearance of antipyrine.

Evaluation of drug absorption and presystemic metabolism using an in situ intestinal preparation.

An in situ rat intestinal preparation was modified to include portal and jugular venous blood collection techniques as well as sampling from the intestinal lumen. Viability could be maintained for 3 h. The utility of the preparation was examined by studying the disposition of four model drugs, each with differing characteristics with respect to absorption and presystemic metabolism.

Hydroxylation and glucuronidation of various xenobiotics by hepatic microsomes from the fetal lamb, pregnant ewe and human fetus.

The ability of microsomes isolated from liver of pregnant ewes and their fetuses at near term to catalyze the biotransformation of benzo[a]pyrene, hexobarbital, meperidine, methadone and morphine was investigated. Cytochromes P-450 and b5, NADPH and NADH cytochrome c reductase, methadone and meperidine N-demethylase and morphine glucuronyltransferase activities were detected in microsomes from both maternal and fetal livers. Fetal hepatic microsomes however, lacked the ability to catalyze the hydroxylation of hexobarbital and benzo[a]pyrene.

Plasma protein binding of bepridil.

The binding of the calcium-channel blocking agent, bepridil HCl (Vascor), to plasma proteins was investigated using radiolabeled bepridil and equilibrium dialysis. Greater than 99.7% of added bepridil-14C was found to freshly collected human plasma.

High levels of methylxanthines in chocolate do not alter theobromine disposition.

Theobromine disposition was measured twice in 12 normal men, once after 14 days of abstention from all methylxanthines and once after 1 week of theobromine (6 mg/kg/day) in the form of dark chocolate. Mean theobromine t 1/2, apparent volume of distribution, and clearance after abstinence from all methylxanthines were 10.0 hours, 0.

Theobromine kinetics and metabolic disposition.

Metabolism and kinetics of a single oral dose of 30 microCi 8-14C-theobromine with 10 mg/kg theobromine sodium acetate were studied in six healthy, nonmedicated, nonsmoking men after 14 days' abstention from all methylxanthine sources. Identification and quantitation of metabolites in plasma and urine both by HPLC and by thin-layer chromatography coupled with radiography indicated that theobromine was predominant in plasma. For urine, both methods identified theobromine as well as 7-methylxanthine, 7-methyluric acid, 3-methylxanthine, 6-amino-5[N-methylformylamino]-1-methyluracil, and a small amount of 3,7-dimethyluric acid as the metabolites of theobromine.

Localized and systemic effects of environmental ammonia in rats.

The purpose of this study was to determine if environmental ammonia is absorbed through the lungs of rats into the blood and, in turn, exerts an effect on blood pH, blood gases, and hepatic drug metabolizing enzyme activity. In phase 1 of the study, rats with surgically implanted aortic cannulas were exposed to varying environmental ammonia concentrations (15 to 1157 ppm). Blood pH, pCO2, pO2, and blood ammonia concentrations were measured at 0, 8, 12, and 24 hours post-exposure.

Influence of different forms of tobacco intake on nicotine elimination in man.

In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by smoking a cigarette containing a standardized amount of nicotine, whereas in the third experiment nicotine was injected intravenously as a single tracer dose of 14C-nicotine. In contrast to cigarette smokers, naive and habituated snuff dippers had similar mean plasma nicotine t1/2 beta.

Smoking-induced changes in nicotine disposition: application of a new HPLC assay for nicotine and its metabolites.

A sensitive, rapid high-pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of 14C-nicotine in normal, carefully matched smokers and nonsmokers. The elimination half-lifes of nicotine and cotinine were shorter in smokers than in nonsmokers. Also consistent with an inductive effect of smoking was the increased nicotine elimination rate constant in smokers, but smoking induced more complex kinetic changes: nicotine volume of distribution was diminished in smokers, whereas nicotine clearance and area under the concentration-time curve were unchanged.

Drug disposition during pregnancy.

This review examines the literature on drug disposition during human pregnancy. Drugs are considered on the basis of their mode of excretion and hepatic extraction ratio in order to assess the general effects of pregnancy on drug disposition. Pregnancy increases clearance of drugs whose excretion is predominantly renal and related to creatinine clearance but fails to change clearance of parenterally administered drugs that are extensively metabolized by liver and have a high hepatic extraction ratio.