In Part 2 of this second annual panel discussion, Jeff Goldsmith, Barbara LeTourneau, Uwe Reinhardt, and physician executives from three physician practice management companies (PPMCs) examine this burgeoning new industry. They grapple with questions (and occasionally with each other), such as: Are PPMCs delivering what they promise? What will separate successful PPMCs from the rest? When PPMCs win, who loses? What value do PPMCs add to health care? What lies ahead for this industry? Could Wall Street pressure cause PPMCs to put profit ahead of physicians and patients? And, what roles will physician executives play in PPMCs?

Evaluation Studies as Topic↗

PubMedDate not supplied

Absorption and disposition of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, WIN 35,833, in rats, monkeys, and men.

2-[4-(2,2-Dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, Win 35,833, was readily absorbed after oral administration; in rats, rhesus monkeys, and human volunteers, peak concentrations of drug in plasma were attained within 2 hr of medication. The time-concentration curve of administered drug was biphasic in monkeys and men, while in rats the kinetics of a one-compartment model were observed. Distribution studies of 14C-labeled drug in the rat showed that most of the radioactivity was excreted in the feces and that significant quantities of 14C were sequestered by depot fat. Monkeys and human subjects both eliminated Win 35,833 primarily through the kidneys. The drug was excreted in rat bile and human urine, both as the free acid and conjugated with glucuronic acid. At physiological concentrations, Win 35,833 was extensively bound to rat, monkey, and human plasma proteins. A gas-chromatographic method for the analysis of drug in plasma, urine, or bile gave a linear relationship between peak height ratios and concentrations, in the range of 1-60 mug/ml.

Animals↗

PubMedDate not supplied

O-Demethylation of p-nitroanisole by Escherichia coli. Stimulation by phenobarbital.

Intact cells of the bacterium Escherichia coli ATCC 11229, can convert p-nitroanisole into p-nitrophenol. The presence of phenobarbital in the culture medium during growth of the cells results in an inhibition of bacterial cell mass and an increased ability of the bacterial cell to carry out the O-demethylation reaction. There was a linear relationship between the amount of product formed and the bacterial cell mass in the incubation mixture. Varying the substrate concentration gave a concomitant change in activity, defined as the amount of product formed per mg of bacterial cell mass per 150 min. The optimum temperature for the production of p-nitrophenol by the stimulated cells was 33 degrees C; 7.0 was the pH optimum.

Escherichia coli↗

PubMedDate not supplied

Absorption, excretion and disposition of cyclindole in laboratory animals and human volunteers.

Radioactivity from orally administered single doses of cyclindole-14C was excreted primarily in the urine of the rat (99%/48 hr), monkey (80%/120 hr), and dog (70%/144 hr). Approximately 38-58% of a daily dose of cyclindole was recovered from 24-hr human urine, as determined by gas chromatography. Substantial amounts of unchanged drug were voided by dogs. Cyclindole was metabolized primarily by N-demethylation and/or hydroxylation in the 7-position. Hydroxylation at the 6-carbon atom was of minor importance in humans only; none of the animal species excreted the 6-hydroxy metabolite. Dogs were capable of N-demethylation, but no metabolites oxidized at the 6- or 7-carbon atoms were detected in dog urine.

Animals↗

PubMedDate not supplied

Absorption and disposition of oxarbazole in man and laboratory animals.

Oxarbazole (9-benzoyl-1,2,3,4-tetrahydro-6-methoxycarbazole-3-carboxylic acid) was absorbed by human volunteers, rats, dogs, guinea pigs, and monkeys. In all species of laboratory animals studied, the major urinary metabolite was the product of O-demethylation, 9-benzoyl-1,2,3,4-tetrahydro-6-hydroxycarbazole-3-carboxylic acid; this metabolite was conjugated in all species except the guinea pig. The dog and monkey excreted small quantities of a conjugate of 1,2,3,4-tetrahydro-6-methoxycarbazole-3-carboxylic acid in the urine. Enterohepatic circulation was demonstrated in bile duct-cannulated rats, in which almost 90% of the radioactivity of a dose of 14C-oxarbazole had been excreted into the bile within 24 hr. At the time of peak blood radioactivity, intact oxarbazole was the major constituent circulating in the bloodstream of rats and monkeys that had received 14C-oxarbazole orally. The clearance of either intact oxarbazole in man and guinea pig, or undifferentiated radioactivity in rat, dog, and monkey, did not follow the kinetics of a simple model.

Absorption↗

PubMedDate not supplied

Seclazone: biotransformation during absorption in the rat, binding in plasma, and disappearance from plasma in the dog.

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Animals↗

PubMedDate not supplied

Analysis of iosulamide in plasma and urine: application to intravenous pharmacokinetics in rhesus monkey.

A sensitive, specific, high-performance liquid-chromatographic method for the determination of iosulamide in plasma and urine is described. The method was used to determine pharmacokinetic parameters of iosulamide after intravenous administration to rhesus monkeys. The mean (+/- SE) distribution and disposition half-lives were 0.19 (+/- 0.03) and 1.5 (+/- 0.3) hr, respectively. The mean (+/- SE) model-dependent and model-independent volumes of distribution at steady state were 0.41 +/- (0.078) and 0.49 (+/- 0.039) liters/kg, respectively. Total urinary excretion of iosulamide represented a mean (+/- SE) of 12.5 (+/- 0.6)% of the administered dose and was virtually complete in 3 hr. The results of the pharmacokinetic study indicate that iosulamide is rapidly cleared from the body and that renal clearance is a minor route of elimination from the body.

Animals↗

PubMedDate not supplied

Metabolism of arildone, an antiviral agent, in laboratory animals.

After arildone administration, four compounds were identified in the excreta of laboratory animals: unchanged drug, arildone; the O-desmethyl metabolite, 4-[6-(2-chloro-4-hydroxy)phenoxy]hexyl-3,5-heptanedione; the sulfate ester of 2-chloro-4-methoxyphenol; and a labile conjugate of chlorohydroquinone, tentatively characterized as the sulfate ester. The concentrations of each of these were determined in the urine and/or plasma of rats, dogs, and mice after administration of 14C-arildone.

Animals↗

PubMedDate not supplied

Metabolism and disposition of sulfinalol in laboratory animals.

Peak levels of radioactivity in blood occurred 1.0 hr after oral administration of 3H-sulfinalol hydrochloride to rats, dogs, and monkeys. The plasma decay curve for intact sulfinalol in the dog was biphasic, with apparent first-order half-lives of 0.55 and 6.2 hr. Rats excreted 42.5% of the dose in the urine and 31.8% in the feces after 24 hr. Urinary and fecal recovery were 53.8% and 41.2%, respectively, after 10 days for dogs and 57.8% and 38.0%, respectively, after 9 days for monkeys. Free sulfinalol (11.8% of the dose) was the major component in dog feces with lesser amounts of the sulfide and sulfone metabolites, also in the unconjugated form. All metabolites in dog urine were conjugated with glucuronic acid, with sulfinalol (28.5%) and desmethylsulfinalol (8.5%) representing the major constituents, whereas the sulfone and sulfide metabolites were minor ones. Monkey feces contained primarily unconjugated forms of the desmethyl sulfide metabolite (17.0%) and sulfinalol (7.5%); lesser amounts of desmethylsulfinalol and the sulfone metabolite were present. Desmethylsulfinalol (8.7%) and its sulfate (7.0%) and glucuronide (4.0%) conjugates were the major urinary metabolites in the monkey; sulfinalol (1.4%), its glucuronide conjugate (5.1%), the desmethyl sulfide metabolite (and its sulfate conjugate), and the sulfone metabolite were also present.

Animals↗

PubMedDate not supplied

Metabolism of amrinone in animals.

The biotransformation of 14C-amrinone was studied in rats, dogs, and monkeys by automated gradient high-performance liquid chromatography. The major pathways of metabolism elucidated are: A) glucuronidation at the primary amino nitrogen atom and/or the enolized oxygen atom of the pyridone ring; B) addition of glutathione at the pyridone 2-position and ultimate hydrolysis of this compound to the 2-S-cysteinyl metabolite; C) formation of the primary amino N-acetyl derivative and subsequent oxidation of this to the corresponding N-glycolate. In each species studied, urine was the primary route of elimination and unchanged amrinone was the major urinary excretion product, the other known pathways being: rat, A and C; dog, A and B; monkey, A.

Administration, Oral↗