Adsorbent and cathartic inhibition of enteral drug absorption.

The effects on absorption of drugs given by mouth of adsorbents (charcoals and resins) and cathartics (osmotic and oil) were studied in vitro and in vivo using acetaminophen (paracetamol) as a test drug. In vitro adsorption isotherms were measured at 37 degrees C in simulated gastric and gastric plus intestinal juices. Maximum binding capacity (MBC) of 16 charcoals and resins varied 30-fold, from 0.36 to 9.32 mol/kg. Dissociation constants varied directly with MBC. In vitro adsorption was little changed by addition of d-mannitol and d-sorbitol, N-acetylcysteine (NAC) or l-methionine. Acetaminophen (0.6 g/kg by orogastric tube) was given to 17 dogs protected by i.v. injections of NAC and methylene blue. One minute later, dogs were given: 1) water; 2) Norit A or Nuchar 1110 charcoal, 3 g/kg; 3) d-mannitol and d-sorbitol, 2 g/kg or castor oil, 3 ml/kg; or 4) both charcoal and either d-mannitol and d-sorbitol or castor oil. Cathartics alone decreased the area under plasma acetaminophen concentrations 15 to 30%. Charcoals alone reduced the area under plasma acetaminophen concentration 93%. Each cathartic diminished the charcoal inhibition of acetaminophen absorption. In mice given acetaminophen by orgastric tube, the acute lethality was decreased more by a new petroleum-based charcoal than by standard wood-based charcoals. Reduction of acetaminophen lethality in mice paralleled the in vitro MBC of adsorbents. Charcoals did not avidly adsorb l-methionine or NAC in vitro. Charcoal did not decrease the l-methionine or NAC protection of acetaminophen-poisoned mice. Charcoals with large MBC diminish absorption and lethality of acetaminophen taken by mouth; cathartics have little effect on acetaminophen absorption.

Professional review of laboratory utilization.

Overutilization of laboratory procedures is a significant problem, particularly in teaching institutions. The purpose of this study was to assess laboratory utilization patterns on the medical service of a university hospital, comparing data from implicit peer review by a pathologist with those from a group of practicing primary care physicians. Also, utilization of the most frequently ordered laboratory tests was compared with that of less common procedures. For charts reviewed both by the pathologist and by a panel of primary physicians, the pathologist found 26.5 per cent of tests unnecessary, while the primary physicians found 42.8 per cent unnecessary. The ten most frequently ordered tests had a significantly higher rate of overutilization than all other tests. Attempts to modify physicians' laboratory utilization should include concomitant peer review of the most commonly ordered procedures.

Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene.

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130-mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and in former heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, "maintenance" patients exhibited steady-state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 2210 ml/min, P half-life (t 1/2) increased from 3.3 to 11.8 hr, NP t 1/2 increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of first-pass elimination of P result in variability in plasma P and NP that may contribute to P-induced toxicity.

The urinary excretion profiles of naltrexone in man, monkey, rabbit, and rat.

A gas-chromatographic method has been developed for the simultaneous determination of naltrexone, alpha-naltrexol, and beta-naltrexol as trimethylsiyl derivatives. Analysis of urine from rabbit, monkey, and rat demonstrated that, like man, these species reduce naltrexone primarily to beta-naltrexol. In naltrexone maintenance patients receiving 125 mg po three times per week, an average of 37% of the dose was recovered in 48-hr urine as free naltrexone (0.8%), conjugated naltrexone (7.6%), free beta-naltrexol (16.8%), and conjugated beta-naltrexol (11.8%). Thirty-four percent of the dose appeared in 0-24 hr and 3% during 24-48 hr. The ratio of beta-naltrexol to naltrexone rose from 2 at 0-4 hr to 34-48 hr. Monkeys receiving a daily dose of 12 mg/kg po, chronically, excreted very little free beta-naltrexol and exhibited an apparent sex-related difference in excretion patterns, with females excreting more than twice as much total base as males. Rabbits given a dose of 30 mg/kg ip for 4 days excreted conjugated naltrexone as the predominant urinary metabolite, accounting for 80% of total base recovered in 24 hr. In rats receiving 100 mg/kg po, less than 1% of the administered dose could be accounted for in the 24-hr urine, indicating that although the beta-naltrexol is produced as a urinary metabolite, other means of disposition of the drug must exist. Thus, in man and the monkey, beta-naltrexol is the predominant and persistent urinary metabolite. Urinary excretion profiles of naltrexone differ greatly between species commonly examined for chronic toxicity studies.