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. Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1- butanone), a reference compound used for model development, disappeared from the intestinal lumen with a half-life of 14 +/- 3 min. When the antiarthritic agent, tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate), was studied in the preparation, it was rapidly absorbed (t1/2 for disappearance from the intestinal lumen = 8 min), achieved plasma concentrations comparable to in vivo data, and underwent little presystemic elimination. In contrast, fenoctimine sulfate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulfate), an antisecretory compound, disappeared more slowly from the intestinal lumen (t1/2 = 60 min), was present in portal plasma, but was not detected in systemic plasma. Extensive hepatic first-pass elimination of fenoctimine was evident. Tolmetin glycine amide (N-([1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl)glycine), a tolmetin prodrug, disappeared from the intestinal lumen very slowly (t1/2 approximately 3 h) compared with the other agents tested. It was determined that this drug was being hydrolyzed presystemically to tolmetin by the intestinal mucosa and the liver. These results establish the utility of this intestinal preparation for studying drug absorption and presystemic elimination.

Pharmacokinetics of chlorzoxazone in humans.

Twenty-three normal male subjects received 900 mg of acetaminophen and 750 mg of chlorzoxazone as an oral suspension. Analysis of plasma samples indicated a rapid absorption and rapid elimination of chlorzoxazone. Average values of the elimination half-life and plasma clearance were 1.12 +/- 0.48 hr and 148.0 +/- 39.9 ml/min, respectively. Analysis of urine samples showed that chlorzoxazone was eliminated from the body as the glucuronide conjugate of the intermediate metabolite 6-hydroxychlorzoxazone, to the extent of 74% of the dose. The plasma and the urinary excretion data were fitted to theoretical equations, and excellent fits were obtained using a five-parameter pharmacokinetic model.

A preliminary study of sex-related differences in prolactin responses to dopamine blockade and insulin hypoglycemia and in penfluridol plasma levels in schizophrenic patients.

Twelve healthy chronic schizophrenic patients were treated with the long-acting oral dopamine (DA) receptor blocker penfluridol (100 mg orally) for 6 weeks. Plasma prolactin (PRL) levels were measured during insulin-tolerance tests (ITT) performed at the end of the drug-free period (7-10 days) and during weeks 1 and 6 of penfluridol treatment. Simultaneous PRL and penfluridol plasma levels were determined just prior to, and at 8, 72 and 120 h after penfluridol administration during weeks 1, 5, and 6. During penfluridol treatment women (N = 4) had a greater increase in their maximal PRL increments after ITT as compared to the men (N = 8). Analyses of (peak) plasma penfluridol and PRL concentrations 8 h after penfluridol administration revealed a trend towards lower plasma penfluridol levels during weeks 5 and 6 and significantly higher PRL levels in women compared to men during weeks 1 (P less than 0.01), 5 (P less than 0.02), and 6 (P less than 0.02). The consistent sex-related differences in the PRL responses to DA blockade, and to insulin-induced hypoglycemia and in the penfluridol plasma levels in our study support the view that sex-related changes need to be considered not only in the hormonal responses to various pharmacological agents, but also in the assessment of the plasma levels of these drugs.

Disposition of zomepirac sodium in man.

Five healthy male human subjects were administered 200 mg oral solution doses of zomepirac-14C sodium. Plasma and urine samples were analyzed for zomepirac, hydroxyzomepirac, and zomepirac glucuronide. Zomepirac was the major circulating compound, with zomepirac glucuronide and hydroxyzomepirac accounting for the remainder of the radioactivity. Elimination half-lives for zomepirac, zomepirac glucuronide, and hydroxyzomepirac were 7.6, 8.2, and 7.8 hours, respectively. The dose was completely recovered in the urine (95 per cent in 72 hours). Zomepirac glucuronide constituted up to 90 per cent of the urinary radioactivity, with zomepirac and hydroxyzomepirac about 5 per cent each. The urinary zomepirac was probably present as a result of hydrolysis of zomepirac glucuronide. The plasma clearance of zomepirac was 189 +/- 23 ml/min. The metabolites were cleared by the kidney at rates of 343 +/- 88 ml/min (zomepirac glucuronide) and 339 +/- 88 ml/min (hydroxyzomepirac). Thus, metabolic clearance appears to be the sole mode of zomepirac elimination. The metabolites are then rapidly cleared by the kidneys.

Quantitative GLC determination of oxycodone in human plasma.

A GLC assay was developed for the determination of oxycodone levels in human plasma using a nitrogen-specific detector. The assay was developed for use in bioavailability studies of therapeutic doses of oxycodone. After ingestion of a commerical tablet containing 4.5 mg of oxycodone hydrochloride and 0.38 mg of oxycodone terephthalate by six volunteers, the mean peak oxycodone concentration in plasma was 18.4 ng/ml at 1 hr.