Michael Kraml

The Metabolic Disposition of Etodolac in Rats, Dogs, and Man

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs. Serum levels in all species were generally dose-related. The elimination portion of the serum drug concentration/time curves was characterized by several peaks, which in rats were shown to be due to enterohepatic circulation. Tissue distribution studies in rats showed that radioactivity localized primarily in blood vessels, connective tissue, and highly vascularized organs (liver, heart, lung, and kidney) and that the rate of elimination of radioactivity from tissues was similar to that found in the serum. The apparent elimination half-life of etodolac averaged 17 hr in rats, 10 hr in dogs, and 7 hr in man. Etodolac was extensively bound to serum proteins. Liver microsomal cytochrome P-450 levels were unaltered in rats given etodolac daily for 1 week. The primary route of excretion in rats and dogs was via the bile into the feces. Preliminary biotransformation studies in dogs showed the presence of the glucuronide conjugate of etodolac in bile, but not in the urine. Glucuronide conjugates were not seen in the rat. Four hydroxylated metabolites in rat bile were tentatively identified. It was concluded that, in rats and dogs, etodolac is well absorbed, is subject to extensive enterohepatic circulation, undergoes partial biotransformation, and is excreted primarily into the feces.U

The pharmacokinetics of etodolac in serum and synovial fluid of patients with arthritis

The pharmacokinetics of etodolac have been evaluated in five patients with arthritis given 200 mg etodolac, twice daily, at 12‐hour intervals, for 7 days. Albumin and total protein concentrations were markedly lower in synovial fluid than in serum, and etodolac free fraction was significantly higher. Etodolac readily penetrated into the synovial fluid, and in the postdistributive phase the concentration of free etodolac (i.e., the drug responsible for pharmacologic activity) remained higher than that in serum at all times. No differences in the half‐life of etodolac elimination were noted.

Disposition of a new tetrahydrocarbazole analgesic drug in laboratory animals and man

1. The disposition of AY-30,068 (I), a new tetrahydrocarbazole analgesic drug, was studied in mice, rats, dogs, rhesus monkeys, and man. 2. Oral doses of the 14C-labelled drug in aqueous solution were well absorbed in rodents, but absorption of oral doses of the crystalline drug in dogs was poor. Due to the virtual absence of serum metabolites in rats and dogs, the bioavailability of I was nearly identical to the extent of absorption. Although a small first-pass effect was observed in mice, unchanged I represented a major portion of serum radioactivity. 3. A linear increase in the serum concentrations of I occurred at doses between 0.05 and 25 mg/kg in rats, 0.1 and 50 mg/kg in dogs, and 1-160 mg in man. In rhesus monkeys given a 0.5 mg/kg oral dose, the Cmax and AUC of I were similar to values obtained following a corresponding dose in dogs. 4. After i.v. administration of a 1.0 mg/kg dose the terminal elimination half-life (t1/2 beta) of I was 4 h in mice and 9-10 h in rats and dogs. In rodents, dogs, and several human subjects, the elimination of I was interrupted by secondary peaks. Enterohepatic circulation was confirmed in bile duct cannulated rats, where the t1/2 beta of I was decreased to 2.4 h. In rodents the serum clearance and apparent volume of distribution of I were 0.04-0.2 l/kg.h and 0.5-0.8 l/kg, respectively, and 0.6 l/kg.h and 9.8 l/kg in dogs. 5. In rodents and dogs dosed with 14C-labelled I, radioactivity was excreted almost entirely in the faeces. No unchanged I was detected in rat bile, while about 70% of the radioactivity corresponded to conjugates of parent drug.

Etodolac kinetics in the elderly

The effects of age and chronic dosing on the pharmacokinetics of the anti‐inflammatory drug etodolac were evaluated in healthy young subjects, healthy elderly subjects, and elderly patients with Osteoarthritis. After either single or chronic (7 days) dosing, both the healthy elderly subjects and the elderly patients with Osteoarthritis had values for etodolac peak concentration, time to reach peak concentration, the AUC from 0 to 24 hours, elimination t½, and free fraction that did not differ significantly from those in the young (control) subjects. Despite the expected increases in the peak concentration and AUC from 0 to 24 hours for all groups after chronic dosing, there were no changes in etodolac free fraction, time to peak concentration, or t½. Because significant accumulation of etodolac was not observed in our elderly participants, adjustment of dosage when elderly subjects receive etodolac therapy is not indicated.

A gas-liquid chromatographic determination of p-chlorophenoxyisobutyric acid and its comparison to an ultra violet method

1. A gas-liquid chromatographic procedure for the determination of p-chlorophenoxyisobutyric acid (CPIB) has been elaborated and compared to the UV spectrophotometric procedure of Barrett and Thorp. 2. Both methods are specific when used to determine CPIB levels in normal sera from laboratory animals or humans treated with clofibrate (Atromid-S). Serum from patients treated with other drugs or abnormal sera from patients affected with a variety of diseases will often contain high and fluctuating levels of non-specific UV absorbing substances and this usually precludes the use of the UV procedure. 3. The GLC method is also applicable to the analysis of CPIB in urine samples.

Metabolic disposition and pharmacokinetics of pelrinone, a new cardiotonic drug, in laboratory animals and man

SummaryThe metabolic disposition of pelrinone, a cardiotonic drug, was studied in mouse, rat, rabbit, dog, monkey and man. Pelrinone was rapidly and extensively absorbed in rodents, dogs, monkeys and man. Except in rabbits, the major portion of the serum radioactivity was due to parent drug. Pelrinone was moderately bound to human serum proteins and weakly bound to serum proteins from animals. Radioactive compounds were rapidly eliminated from rat tissues with the highest concentrations found in organs associated with absorption and elimination. After a 1.0 mg/kg i.v. dose, the rapid elimination of pelrinone from mouse, rat and dog serum precluded estimation of an elimination half life (t1/2). However, after higher oral or i.V. doses, a more prolonged elimination phase was apparent and the t1/2 of pelrinone ranged from 8–10 h in rodents and dogs. In human subjects given escalating oral or i.v. doses of pelrinone, the elimination t1/2 was independent of dose and averaged 1–2 h. The serum AUC of pelrinone was linearly dose-related following oral doses up to 20 mg/kg in dogs and 100 mg in man. In mice, a greater proportional increase in AUC occurred between oral doses of 2–100 mg/kg while in rats, the serum AUC increased in less than proportional manner from 10–200 mg/kg p.o. In ell species, radioactive compounds were excreted mainly in the urine. No metabolites were detected in dog and human urine while small amounts of unconjugated metabolites were excreted in mouse and rat urine.

Comparative Pharmacodynamics and Pharmacokinetics of Conventional and Long-Acting Propranolol

This investigation was conducted to compare the pharmacokinetic and pharmacodynamic effects of single and multiple doses of conventional propranolol and long‐acting propranolol in healthy human volunteers. Two double‐blind, randomized, double‐crossover, Latin square studies were carried out. One study evaluated long‐acting propranolol 160 mg/d, conventional propranolol 40 mg qid, or placebo for seven days in 24 men. The other study compared long‐acting propranolol 80 mg/d, conventional propranolol 20 mg qid, or placebo for seven days in 27 men. At specific times after the administration, blood samples were obtained, and heart rate and blood pressure were measured; exercise tests were done both on the first day and at steady state (day 7). In both studies, the area under the plasma propranolol concentration‐time curve and the peak concentration were significantly less (P < .0001) after the administration of long‐acting propranolol compared with conventional propranolol on both day 1 and day 7; in addition, the elimination half‐life was longer after administration of the long‐acting preparation (9 hr) compared with that following the conventional dosage form (4 hr). Both conventional and long‐acting propranolol significantly decreased the exercise heart rate at each of the selected time points (P < .05) compared with placebo. Reduction in exercise heart rate was greater with conventional propranolol than with the long‐acting formulation, but the differences were not statistically significant, when exercise was performed only at trough levels of the conventional drug. The decreases in exercise heart rate were correlated with plasma propranolol concentrations.

The metabolic disposition of acifran, a new antihyperlipidemic agent, in rats and dogs

The metabolic disposition of the antihyperlipidemic agent acifran (AY-25, 712) was determined in rats and dogs. The synthesis of 14C-labelled acifran is described. Serum levels of 14C and acifran were measured in rats and dogs after p.o. and i.v. administration of 14C-acifran at a dose of 10 mg/kg. Over 80% of the 14C in serum was due to acifran. The drug was rapidly absorbed and the pharmacokinetics, unaffected by increasing the dose or by daily multiple doses, were characterized by a two-compartment open model. Food reduced the bioavailability of acifran by 27% in the dog. About 65% of the dose was absorbed in rats, and at least 88% in dogs. The elimination t 1/2 of acifran from serum was 1.5 h in the rat and 3 h in the dog. Acifran was partially bound to serum proteins, man greater than rat greater than dog; the drug was found to displace protein-bound warfarin in rat and dog, but not in human serum. Radioactivity did not tend to accumulate in tissues, except for the kidney, where the 14C concentration was five times higher than in the serum; elimination of 14C from all the tissues was similar to that from serum. Most of the absorbed dose was excreted in the urine. Acifran did not undergo enterohepatic circulation in the rat. Virtually all the urinary 14C in both species was due to the unchanged compound. In conclusion, the disposition of acifran was similar in rats and dogs. The drug was rapidly absorbed and eliminated, and underwent no detectable biotransformation. There was no tissue retention and excretion was mainly in the urine.

Prodolic Acid: Analysis and Disposition Studies in Rats and Dogs

1. A specific fluorimetric method for the determination of prodolic acid in serum has been elaborated and has a limit of detection of 2 microgram/ml. 2. Common anti-inflammatory drugs do not interfere with the method. 3. In rats and dogs, prodolic acid is rapidly absorbed and has a short half-life of elimination. 4. The rate of elimination was marked by secondary rises in the blood level profile which were shown to be due enterohepatic recirculation of prodolic acid. 5. Prodolic acid is highly bound to serum protein.

Butriptyline: Improved gas-liquid chromatographic method using a nitrogen-phosphorus detector for its determination in serum

We report a sensitive and specific method for the determination of butriptyline concentrations in serum by gas-liquid chromatography with a nitrogen phosphorus detector. The detection limit is 2 ng/ml, based on 3 ml of serum or plasma. The method has been validated in human volunteers receiving a single oral dose of 75 mg butriptyline hydrochloride.