Eric C. Schreiber

Pharmacokinetics of Cephalosporin Antibiotics: Protein-Binding Considerations

The therapeutic activity of antibiotics depends on several factors including absorption, elimination kinetics, distribution in the body, minimal inhibitory concentrations (MIC), stability against enzymes, and plasma-protein binding. Some of these factors are interrelated, for example, the extent of protein binding of an antibiotic influences its elimination kinetics, distribution into tissues, MIC, and antibacterial activity. To evaluate the potential efficacy of an antibiotic, it is important to know the extent of its binding to plasma proteins especially since the protein-bound fraction of the antibiotic is devoid of antibacterial activity. Cephalosporins are a new class of broad-spectrum antibiotics that bind to plasma proteins in different degrees. Reported values for protein binding range from 6% for cephradine to 92% for cefazolin. The effects of protein binding of some of the commonly used cephalosporins on antibacterial activity and several pharmacokinetic parameters are discussed in this communication.

The effect of analgesics on the hexobarbital sleeping times of rats, dogs, and rhesus monkeys: A species difference

Abstract Bandol ® , (2-ethoxy- N -[2-(methylphenethylamino)-ethyl]-2,2-diphenylacetamide hydrochloride), an analgesic, increases the hexobarbital sleeping times of rats, dogs, and rhesus monkeys. The degree of increase is greater in rats than in dogs and monkeys. Darvon ® , another analgesic, increases sleeping times to about the same extent in all three animal species. In rats, Bandol is more effective than Darvon. In dogs and monkeys, Bandol is no more potent than Darvon in increasing sleeping times. Electron micrographs of sections of liver from rats that received various chronic doses of Bandol revealed some proliferation of the smooth endoplasmic reticulum. If any induction of microsomal enzymes has occurred in the rats that received Bandol chronically, other properties of the compound overshadow this effect resulting in a net increase of the hexobarbital sleeping times.

Disposition of [14C]nadolol in dogs with reversible renal impairment induced by uranyl nitrate.

Disposition of [ 14 C]Nadolol in Dogs with Reversible Renal Impairment Induced by Uranyl Nitrate. Singhvi, S. M., Heald, A. F., Murphy, B. F., DiFazio, L. T., Schreiber, E. C., and Poutsiaka, J. W. (1978). Toxicol. Appl. Pharmacol. 43 , 99–109. A model for studying the effects of renal impairment on the disposition kinetics of a drug has been developed. Intravenous uranyl nitrate (0.5 mg/kg) was used to produce reversible renal impairment in dogs. The disposition kinetics of [ 14 C]nadolol were determined in two unanesthetized bile duct-cannulated beagles before and 3, 7, 11 [one dog], and 18 days after administration of uranyl nitrate. Creatinine was included with the [ 14 C]nadolol dose to permit the estimation of glomerular filtration rate (GFR) in each experiment. Over a period of 3 to 7 days, the GFR in one dog declined to about 25% of normal, followed by complete recovery in 18 days. There was a decrease in the renal clearance of nadolol that paralleled the degree of renal impairment. The disposition half-life of [ 14 C]nadolol increased from a control value of 3.6 to 7.7 hr on Day 7 and decreased to 4.5 hr by Day 18 when the GFR had returned to normal. In the other dog, the disposition half-life of [ 14 C]nadolol increased from a control value of 4.3 to 5.2 hr on Day 7 when the GFR was 64% of normal. In both dogs, a linear relationship was observed between the renal clearance of [ 14 C]nadolol and the GFR. Other pharmacokinetic parameters were also compared at different degrees of renal impairment. Renal impairment had a marked effect on the disposition of nadolol in dogs.

Metabolic dynamics of dicyclomine hydrochloride in man as influenced by various dose schedules and formulations

Abstract Metabolic studies were conducted on each of four normal human male subjects, 20–30 years of age, weighing within the range of 150–180 pounds, to compare the absorption, plasma levels, and excretory routes of 14C-labeled dicyclomine hydrochloride utilizing four regimens, differing in dosage and form. Control and experimental periods, each of 7 days duration, were undertaken using fractional collection of blood, urine, and stool specimens. The four regimens studied in each subject included: (1) 3 × 10 mg (8 μCi/10 mg) capsules po; (2) 1 × 10 mg (8 μCi/10 mg) capsule po at 0, 4, and 8 hours; (3) 1 × 30 mg (24 μCi/30 mg) tablet in a continuous release form, po; (4) 10 mg (8 μCi/10 mg) in 10 ml total volume, iv. The data indicate dicyclomine hydrochloride to be rapidly absorbed following oral administration; the drug and/or its metabolites are detectable in the urine within 1 hour. The principal route of elimination is via the urine (79.5% of the dose). Excretion also occurs via the feces, but to a lesser extent (8.4%). The average combined excretory recovery of drug in 4 subjects and 4 drug regimens was 87.9% in the 7 days after drug administration. Little difference in the average urinary recovery (76.3–82.1%) following various modes of administration was noted, suggesting that absorption was essentially complete in all cases including the continuous-release matrix form. Fecal recovery was somewhat more variable (5.2–15.3%).

Species differences in the metabolism of a tricyclic psychotropic agent, SQ 11,290-14C

Abstract The metabolism of SQ 11,290- 14 C (4-[3-(7-chloro-5,11-dihydrodibenz[ b,e ]-[1,4]-oxazepin-5-yl)propyl]-α,β- 14 C 2 -1-piperazineethanol, dihydrochloride) was studied in mice, rats, guinea pigs, hamsters, New Zealand White or Dutch rabbits, monkeys and man after po administration. The excretion of SQ 11,290- 14 C, its metabolites, or both, was chiefly in the feces (with the exception of hamsters and man). Rats and rabbits of either strain excreted 2–5% of the dose—mice and hamsters excreted 20–42%—as 14 CO 2 . Hamsters appeared to excrete radioactivity in a quantitative manner most similar to that observed in man, but the metabolites found in the urine and feces of these 2 species were not similar. The disposition of SQ 11,290- 14 C in albino and pigmented rabbits cannot be distinguished on the basis of the excretion of radioactivity, but different metabolites appear to be excreted in the urine. No unchanged SQ 11,290- 14 C was detected in the excreta of humans. One percent of the dose or less was present as unchanged SQ 11,290- 14 C in the urine of any animal species. In the feces, an average of 2–6% of the dose was excreted by animal species as unchanged SQ 11,290- 14 C. Whereas albino rabbits excreted in the feces only 3.6% of the dose as unchanged drug, Dutch rabbits excreted about 16.7% of the dose as unchanged drug. In those human subjects excreting large amounts of radioactivity as 14 CO 2 , cleavage or degradation of the side chain, or both, rather than hydroxylation of the ring system as had been found previously in dogs, appeared to be a major metabolic pathway.

Chapter 20. Drug Metabolism

Publisher Summary This chapter discusses results of studies focusing on drug metabolism. Considerable effort was expended in 1970 in comparing, among different species, the biotransformation of a particular compound. Such studies point out the difficulty of finding a suitable animal species for toxicity studies that, qualitatively and quantitatively, produces the metabolites that are excreted by man. In a study, seven metabolites of Lu 5-003, a thiophthalane with antidepressive properties, were found in the excreta of rats, dogs, and man. Five of these metabolites, present in all three species, were a result of sulfoxidation, demethylation with subsequent deamination of the side chain, or a combination of these processes. Metabolic alterations of protriptyline were studied in dogs, miniature pigs, and man. In all three species, a primary reaction was oxidation of the cycloheptene moiety, presumably via an epoxide intermediate, yielding, in the urine, mono- and di-hydroxylated metabolites and their conjugates. The metabolism of prazepam, the cyclopropyl derivative of the N -methyl group of diazepam, was studied in man. This compound is slowly absorbed and slowly excreted, primarily as conjugates. Dealkylated prazepam is the only unconjugated metabolite found in urine, whereas 3-hydroxyprazepam and oxazepam were excreted as conjugates.