Serum Elimination Half-life Research Articles

Serum elimination half-life of tamoxifen and its metabolites in patients with advanced breast cancer.

In breast cancer patients discontinuing chronic tamoxifen therapy, the serum elimination of metabolites X, Y and E paralleled that of tamoxifen, whereas that of metabolite Z did not. The serum elimination of tamoxifen and metabolites X and B was increased by amino-glutethimide treatment, whereas that of metabolites Z, Y, and E was not.

Pharmacokinetics of intravenous and oral methimazole following single‐and multiple‐dose administration in normal cats

The pharmacokinetics of methimazole (MMI) administered intravenously and orally were determined in six adult domestic shorthaired cats. There was no significant difference between mean serum MMI concentrations after oral and i.v. administration by 30 min post-MMI administration, indicating relatively rapid and complete absorption of the drug. The bioavailability of MMI ranged from 27% to 100% (mean = 81.1 +/- 11.4%). The mean serum elimination half-life was 6.6 +/- 2.0 h, with a wide range of values (1.9 h to 15.1 h). After repeat i.v. administration of MMI following 2 weeks of oral administration of the drug, no significant difference was found between mean serum concentrations after single-dose and multiple-dose administration. No significant change in serum elimination half-life or total body clearance was found after multiple-dose administration of MMI. Two cats with the longest half-lives (9.9 h and 15.1 h), however, did exhibit markedly shorter t1/2 values (3.5 h and 3.3 h, respectively) after multiple-dose administration. Values for central and steady state volumes of distribution also decreased after multiple-dose administration, possibly indicating saturation of thyroid uptake of MMI with chronic administration. These results indicate that MMI has good oral bioavailability and has a longer mean serum elimination half-life than propylthiouracil, the other anti-thyroid drug that has been evaluated in cats. Although no significant change in mean values occurred after multiple-dose administration of MMI, drug-induced acceleration of metabolism may occur in some cats after long-term MMI administration.

A Phase I Clinical Trial with Gadodiamide Injection, a Nonionic Magnetic Resonance Imaging Enhancement Agent

Twenty adult male volunteers were studied in an unblinded, ascending-dose study to evaluate the safety, tolerance, and pharmacokinetics of intravenously administered nonionic gadodiamide injection. Dosages administered were 0.05, 0.1, 0.2, and 0.3 mmol/kg. Subjects were monitored from 36 hours before, through 72 hours after administration. There were no clinically relevant changes in vital signs or electrocardiograms. No clinically significant changes occurred in blood or urine laboratory parameters, although a tendency for minor, transient elevations in serum iron levels 8 to 48 hours after administration was noted. These changes were not dose-related. Nine of 20 subjects reported at least one adverse event; all events were transient and of mild intensity, the most common being dizziness/lightheadedness and perversion of taste or smell. One subject reported discomfort consisting of mild stinging at the injection site during administration. Gadodiamide was excreted unmetabolized in the urine with greater than 95% recovery at 72 hours after administration. The serum elimination half-life was approximately 70 minutes.

Pharmacokinetic Optimisation of Histamine H1-Receptor Antagonist Therapy

Second-generation, relatively nonsedating histamine H1-receptor antagonists (H1-RA) are extensively used worldwide for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria. Information about the pharmacokinetics and pharmacodynamics of these medications, while still incomplete, is now sufficient to permit optimisation of therapy. Published pharmacokinetic and pharmacodynamic information on these H1-RA is summarised here, and areas where more data are required are delineated. Serum concentrations of most second-generation H1-RA are relatively low, and are usually measured by radioimmunoassay. After oral administration, peak concentrations are observed within 2 or 3 h. Bioavailability has not been well studied, due to the lack of intravenous formulations. Most H1-RA are metabolised in the hepatic cytochrome P450 system: terfenadine, astemizole, loratadine, azelastine, and ebastine have 1 or more active metabolites which are present in serum in higher concentrations than the respective parent compound, and therefore can be measured by high performance liquid chromatography. Cetirizine, an active metabolite of the first generation H1-receptor antagonist hydroxyzine, is not further metabolised to any great extent in vivo, and is eliminated via renal excretion. Levocabastine is also eliminated primarily by excretion. Serum elimination half-life values differ greatly from 1 H1-RA to another, and are 24 h or less for terfenadine, astemizole, loratadine, cetirizine, azelastine and ebastine, and the active metabolites of terfenadine, loratadine and ebastine. The active metabolite of azelastine (demethylazelastine) has a serum elimination half-life value of about 2 days, while that of astemizole (demethyl-astemizole) has a value of 9.5 days. From the few published studies in which the apparent volumes of distribution of the second-generation H1-RA have been calculated, it appears that tissue distribution is extensive. In children, the half-lives of H1-RA are generally shorter than are found in adults; there is no published information on the pharmacokinetics of astemizole, loratadine, azelastine, or ebastine in children. In some elderly adults, terfenadine, loratadine and cetirizine may have longer half-lives than in young healthy adults. There is little published data on the pharmacokinetics of the second-generation H1-RA in patients with impaired hepatic function. The half-life of cetirizine is prolonged in those with impaired renal function. There is a paucity of information on the pharmacokinetics of H1-RA in neonates, in pregnancy or during lactation.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparative study of pharmacokinetics and serum bactericidal activity of ceftizoxime and cefotaxime

Single 2-g intravenous doses of ceftizoxime (CZX) and cefotaxime (CTX) were given over 30 min to 10 adult volunteers in a crossover manner on two separate occasions. Concentrations of CZX, CTX, and the primary metabolite of CTX, desacetylcefotaxime (dCTX), in serum, suction-induced-blister fluid, and urine were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using an extended least-squares modeling program (MKMODEL). CZX exhibited a half-life in serum (2.05 h) longer than that of CTX (1.43 h) but comparable to that of dCTX (2.02 h). The percentage of penetration in blister fluid, estimated by area under the curve ratios, was significantly higher for CZX (164.4%) than for CTX (60.8%). Serum bactericidal activity, determined for volunteer samples at 1, 6, 8, and 12 h after patients were dosed, against clinical isolates of the Bacteroides fragilis group, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Morganella morganii were significantly higher for CZX than those for CTX against members of the family Enterobacteriaceae at all times. Serum bactericidal titers against B. fragilis were also higher for CZX than for CTX at 1 h postinfusion. Neither CZX nor CTX exhibited any bactericidal activity at any other time against the B. fragilis group. In conclusion, the serum bactericidal activity of CZX was greater and more-prolonged than that of CTX against tested strains in spite of the in vitro synergistic contribution of dCTX to CTX, equal serum elimination half-lives of dCTX and CZX, and similar antibacterial activity and similar instability under microbiological testing for CZX and CTX.

Rapid administration of high-dose human antibody fab fragments to dogs: Pharmacokinetics and toxicity

The treatment of drug overdose with drug-specific antibody fragments may require very high antibody doses. To address the feasibility of this therapy, we studied the pharmacokinetics and toxicity of high-dose human nonspecific Fab fragments in beagles. Three dogs received 5.3 g/kg Fab iv over 1 hr. Because nephrotoxicity was observed, three subsequent dogs received 3.2 g/kg. The fraction of the Fab dose excreted in urine (10 ± 6%) was lower than reported values for either high or low doses of Fab in other species. The terminal serum elimination half-life (42 hr for the higher and 48 hr for the lower dose) was also longer than reported values for other species, due to lower renal and nonrenal Fab clearance. Fab administration was tolerated without adverse hemodynamic effects. One of three dogs at each dose developed transient oliguria. All dogs developed a transient but marked increase in the serum creatinine concentration. At 2 weeks creatinine clearance had returned to normal. Urinary protein and albumin excretion at 2 weeks were within the normal range for dogs but were increased over their baseline values. The histology of all organs was normal at 3 weeks by light microscopy, and renal histology by electron microscopy was also normal. The mechanism of Fab nephrotoxicity, not observed previously with high-dose Fab in rats or lower doses of Fab in other species including dogs, is not clear. These data suggest that further study of the potential toxicity of high-dose Fab, and its reversibility, is needed to assess the feasibility of treating drug overdose with this antibody fragment. The long terminal half-life of high-dose Fab in the dog and its low renal clearance contrast with values observed with lower doses of Fab in other species but would not be expected to preclude the use of high-dose Fab for drug overdose.

Comparative efficacy and safety of cefprozil (BMY-28100) and cefaclor in the treatment of acute group A beta-hemolytic streptococcal pharyngitis

Cefprozil (BMY-28100) is a semisynthetic cephalosporin with broad-spectrum antibacterial activity and prolonged serum elimination half-life allowing for once-a-day oral administration. In vitro, cefprozil demonstrates excellent activity against Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefprozil (500 mg once daily) was compared to cefaclor (250 mg three times daily) in an open, randomized, comparative trial for the treatment of acute group A beta-hemolytic streptococcal pharyngitis. Ninety-four patients were enrolled in this study; 53 patients were evaluable for clinical and bacteriological response assessment. Seventy-eight patients were evaluable for safety assessment. Three patients (all in the cefprozil treatment group) required disenrollment because of side effects, mainly nausea. Clinical and bacteriological responses were comparable for both study drugs. Leukopenia and nausea, the most common side effects observed, were more common in the cefprozil-treated group. Cefprozil appears to be an appropriate alternative to cefaclor for the treatment of acute group A beta-hemolytic streptococcal pharyngitis. However, because of the small number of patients eligible for efficacy assessment, a large type II (beta) error was expected in our study, which may have resulted in a potential failure to detect a difference between both treatment groups. A larger study would be required to determine the proper role of cefprozil in the treatment of group A beta-hemolytic streptococcal infections.

The Efficacy of Diuretics in Acute and Chronic Renal Failure

Loop diuretics in high doses are the drugs of choice in the treatment of both acute renal failure (ARF) and chronic renal failure (CRF). Their pharmacokinetic and pharmacodynamic properties give them a high efficacy, even in severely compromised renal function. The serum elimination half-life and duration of action of most loop diuretics are dependent on the glomerular filtration rate and are therefore prolonged in renal failure. Torasemide, a new high ceiling and long acting loop diuretic, is as potent as furosemide (frusemide) in patients with advanced renal failure. Unlike other loop diuretics, the half-life and duration of action of torasemide are not dependent on renal function and the parent drug does not accumulate in renal failure. The extent of metabolism is clinically negligible. A number of studies have demonstrated the efficacy of furosemide, bumetanide, piretanide and torasemide in patients with ARF and CRF. When compared with the other loop diuretics, torasemide has the following advantages: a longer half-life independent of renal function, no indications of toxic side effects and apparently less influence on calciuresis.

A review of the pharmacokinetic profile of temafloxacin.

Temafloxacin is a new fluoroquinolone with potent activity against several important bacteria. Studies in healthy volunteers indicate that the average bioavailability of temafloxacin exceeds 90%, with little intersubject variability. Steady-state peak serum levels are approximately 1 mg/L per 100 mg oral dose administered; thus, the steady-state peak serum level after 600 mg bd oral dosing is approximately 6 mg/L. The long serum elimination half-life (approximately 8 h in patients with normal renal function) allows for single or twice-daily dosing. Approximately 60% of a dose is recovered unchanged in the urine in normal volunteers. Non-renal clearance is approximately 60-80 mL per minute and consists of metabolism (5% of dose), biliary secretion of unchanged drug, and presumptive transintestinal elimination. A doubling of the dosing interval (e.g. from 12 to 24 h) is indicated in patients with a creatinine clearance less than 40 mL/min. No special adjustment of dose is required in those with hepatic dysfunction or the elderly. Studies with temafloxacin show no significant effects on the metabolism of theophylline. Integration of drug pharmacokinetic and pharmacodynamic properties support use of single or twice-daily dosing of temafloxacin.

Rapid Administration of High-Dose Human Antibody Fab Fragments to Dogs: Pharmacokinetics and Toxicity

Rapid Administration of High-Dose Human Antibody Fab Fragments to Dogs: Pharmacokinetics and Toxicity. Keyler, D. E., Salerno, D. M., Murakami, M. M., Ruth, G., and Pentel, P. R. (1991). Fundam. Appl Toxicol 17, 83-91. The treatment of drug overdose with drug-specific antibody fragments may require very high antibody doses. To address the feasibility of this therapy, we studied the pharmacokinetics and toxicity of high-dose human nonspecific Fab fragments in beagles. Three dogs received 5.3 g/kg Fab iv over 1 hr. Because nephrotoxicity was observed, three subsequent dogs received 3.2 g/kg. The fraction of the Fab dose excreted in urine (10 ± 6%%) was lower than reported values for either high or low doses of Fab in other species. The terminal serum elimination half-life (42 hr for the higher and 48 hr for the lower dose) was also longer than reported values for other species, due to lower renal and nonrenal Fab clearance. Fab administration was tolerated without adverse hemodynamic effects. One of three dogs at each dose developed transient oliguria. All dogs developed a transient but marked increase in the serum creatinine concentration. At 2 weeks creatinine clearance had returned to normal. Urinary protein and albumin excretion at 2 weeks were within the normal range for dogs but were increased over their baseline values. The histology of all organs was normal at 3 weeks by light microscopy, and renal histology by electron microscopy was also normal. The mechanism of Fab nephrotoxicity, not observed previously with high-dose Fab in rats or lower doses of Fab in other species including dogs, is not clear. These data suggest that further study of the potential toxicity of high-dose Fab, and its reversibility, is needed to assess the feasibility of treating drug overdose with this antibody fragment The long terminal half-life of high-dose Fab in the dog and its low renal clearance contrast with values observed with lower doses of Fab in other species but would not be expected to preclude the use of high-dose Fab for drug overdose.

Complications of General Anesthesia for Nd:YAG Laser Resection of Endobronchial Tumors

We studied the incidence and mechanisms of cardiovascular complications and postoperative respiratory insufficiency associated with GA and Nd:YAG laser endobronchial tumor resection. The records of 73 patients undergoing 87 procedures were reviewed. Preoperative status, anesthetic methods and perioperative complications were analyzed by multiple regression to determine predictors of outcome. Twenty-three percent of patients had greater than 90 percent mainstem bronchus obstruction. Longer serum elimination half-life of relaxant drug was significantly correlated with longer duration of mechanical ventilation after neuromuscular blockade reversal. Cardiovascular complications were noted in 24 procedures and often required therapeutic intervention. Variables predicting cardiovascular complications included longer duration of GA and increasing age. Perioperative respiratory and cardiovascular complications are common after GA for Nd: YAG laser resection. Short-acting neuromuscular relaxants, careful assessment prior to postoperative extubation, limiting duration of GA and cardiovascular monitoring are recommended when implementing GA for Nd: YAG laser resection of endobronchial tumors.

The phannacokinetics of cefuroxime axetil in the sick elderly patient

The pharmacokinetics of cefuroxime axetil (RS3 formulation) were studied in 20 elderly patients following admission for lower respiratory or urinary tract infection. The mean age was 83.9 years. A 12-hourly dose of 250 mg was given for five days. The mean time to attain maximum serum concentration was 3.2 h with a mean peak concentration of 8.5 mg/l. The mean serum elimination half-life was 3.5 h and the AUC0-infinity 60.4 mg/h.l. There was no accumulation of the drug in the patients studied after five days treatment. The data suggest that the standard dosage regimen is adequate in the sick elderly patient.

Comparative efficacy and safety of cefprozil and cefaclor in the treatment of acute uncomplicated urinary tract infections

Cefprozil is a new oral semi-synthetic cephalosporin with broad antibacterial spectrum and prolonged serum elimination half-life. In vitro, cefprozil demonstrates excellent activity against common urinary tract pathogens such as Escherichia coli and Klebsiella pneumoniae. Cefprozil, 500 mg once a day, was compared to cefaclor, 250 mg three times a day, in an open, randomized, comparative, clinical trial for the treatment of acute, uncomplicated, urinary tract infection. One hundred and two adult patients were eligible for safety evaluation; four patients were excluded due to side-effects (abdominal discomfort, nausea and vomiting). Ninety-eight patients were eligible for evaluation of efficacy. Clinical and bacteriological responses were comparable for both antibiotics. Leucopenia, nausea, and vaginal yeast infections were slightly more common in the cefprozil group. Cefprozil, 500 mg once daily, appears to be an appropriate alternative for the treatment of acute, uncomplicated urinary tract infections.

Allometric analysis of doxycycline pharmacokinetic parameters

Doxycycline serum concentration-time profiles and elimination half-lives in several species were evaluated by allometric techniques. Doxycycline elimination half-life increased with body weight. Interspecies scaling of total or free doxycycline serum concentration-time profiles was possible by use of Dedrick plots with the exception of doxycycline total concentrations in cats. The observed difference in cats was attributed to more extensive binding to plasma proteins.

Regulation of Serum Insulin-Like Growth Factor-I (IGF I) and IGF Binding Proteins during Rat Pregnancy*

Serum concentrations of insulin-like growth factor-I (IGF-I) in rats are reduced dramatically in the latter half of pregnancy, decreasing from 1758 +/- 356 ng/ml at 12 days of pregnancy (mean +/- SD) to 761 +/- 192 ng/ml at 15 days. After parturition, IGF-I increases to nonpregnant values in 4 days. Using ligand blotting, we have demonstrated that most of the serum IGF binding proteins (IGFBPs) are concurrently reduced during pregnancy. IGFBP-3, the predominant IGFBP in nonpregnant serum, is reduced to 1.3% of nonpregnant values by 21 days of pregnancy and begins to rise within 1 h postpartum (PP). The sera of 21-day pregnant (but not nonpregnant) rats degrade IGFBP-3 in vitro, and this degradation is prevented by the protease inhibitor antipain. Decreased serum IGF-I concentrations during pregnancy, therefore, may result from reduced IGFBP-3 concentrations causing increased IGF-I clearance. In addition, steady state IGF-I mRNA and peptide levels in liver are decreased in 21-day pregnant rats (37% and 42% of 4 day PP levels, respectively), suggesting that decreased synthesis of IGF-I may also lead to lower serum IGF-I concentrations. After bolus injection, [125I]IGF-I is cleared from the serum of pregnant rats nearly 5 times faster than that of 4 day PP rats (1.21 vs. 0.25 ml/min/kg, respectively). Urinary clearance is relatively insignificant (less than 4%), and [125I]IGF-I does not cross the placenta. The intermediate distribution phase of IGF-I is slower in pregnant rats than in PP rats (t1/2 alpha, 17.1 vs. 5.4 min), whereas the terminal elimination of IGF-I is twice as fast (t1/2 beta, 228.1 vs. 106.4 min). The prolonged IGF-I distribution phase in the pregnant rats may result from decreased concentrations of 34,000 and 30,000 mol wt IGFBPs, which may transport IGF-I to tissues. The faster serum elimination half-life may result from diminished IGFBP-3, leading to greater IGF-I availability to tissues in pregnancy.

Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia

The pharmacokinetics, pharmacodynamics, and safety of pravastatin, a new selective 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, were evaluated during monotherapy and with subsequent concomitant cholestyramine therapy in 33 patients with primary hypercholesterolemia in this randomized study. After 4 weeks, pravastatin monotherapy (5 mg, 10 mg, and 20 mg twice daily) significantly decreased total cholesterol by 17% to 24% (p less than 0.001 versus baseline) and low-density lipoprotein cholesterol by 23% to 35% (p less than 0.001). High-density lipoprotein cholesterol increased by 8% to 9%, and triglycerides decreased by 6% to 9%. The area under the serum concentration-time curve and maximum serum concentration of pravastatin showed dose-proportionality; time to maximum serum concentration and serum elimination half-life were independent of dose. When added to pravastatin therapy, cholestyramine enhanced the lipid-lowering effects of pravastatin. After 4 weeks of combination therapy, total cholesterol was reduced by 32% to 38% (p less than 0.001 versus baseline), and low-density lipoprotein cholesterol was reduced by 47% to 56% (p less than 0.001). High-density lipoprotein cholesterol increased by 11% to 18% (p less than 0.05). Pravastatin was well tolerated; no clinical adverse events directly attributable to the drug were reported.

New H1‐receptor antagonists: clinical pharmacology

The non-sedating, second-generation H1-receptor antagonists such as terfenadine, astemizole, loratadine and cetirizine differ considerably from each other in their pharmacokinetics and pharmacodynamics. They are generally well absorbed when administered orally. They have extremely variable serum elimination half-life values. The maximum antihistaminic effect of these medications occurs several hours later than peak serum concentrations do. The duration of the antihistaminic effect is much longer than would be predicted from the serum elimination half-life values. The relative incidence of anticholinergic and central nervous system adverse effects caused by these medications is similar to that produced by placebo. The introduction of the second-generation H1-receptor antagonists represents a major advance in symptomatic therapy of allergic disorders such as allergic rhinitis and urticaria.

Diphenhydramine: Pharmacokinetics and Pharmacodynamics in Elderly Adults, Young Adults, and Children

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly

In a double-blind, randomized, crossover study, the H 1-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 ± SD 0.8 years, who ingested single doses of terfenadine, 1 mg/kg (mean dose, 69.6 ± 11.2 mg), and chlorpheniramine, 0.12 mg/kg (mean dose, 8.4 ± 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 ± 3.7 hours. After terfenadine ingestion, significant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 ± 13% to 60 ± 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 ± 15% to 78 ± 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 ± 11.0 hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 ± 11% to 37 ± 11% from 5 to 6 hours. Significant flare suppression occurred from 1 to 12 hours, with maximum flare suppression of 43 ± 14% to 46 ± 19% at 2, 5, and 6 hours ( p < 0.01). Adverse effects, chiefly sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients after receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H 1-receptor-antagonist ingestion.

Effect of amiodarone on non-deiodinative pathway of thyroid hormone metabolism

Amiodarone, an iodine containing anti-arrhythmic drug, causes a significant decrease in molar ratio of daily production rates of T3 and T4 from 0.75 in controls to 0.36 in amiodarone-treated rabbits. A model was constructed from the above data which showed that metabolism of T4 via non-deiodinative pathways (e.g. tetraiodothyroacetic acid and/or conjugates) increased from 29% in untreated controls to 66% in amiodarone-treated rabbits. In this study, we have examined the metabolic clearance rate of tetraiodothyroacetic acid in rabbits given amiodarone (20 mg.kg-1.day-1 ip for 3 weeks) or saline (controls). Serum amiodarone and desethylamiodarone levels under the above experimental conditions were 0.20 +/- 0.067 and 0.17 +/- 0.058 mg/l, respectively, which were in the near-therapeutic range observed in humans. Control and amiodarone-treated rabbits were administered [125I]-tetraiodothyroacetic acid (10 muCi/rabbit) iv and blood was collected at 0.5, 1, 2, 4, 6, 10, 32 and 48 h. Serum tetraiodothyroacetic acid radioactivity was determined by trichloroacetic acid precipitation and ethanol extraction and metabolic clearance rates were calculated from the area under the curve of computer fits to tetraiodothyroacetic acid radioactivity data. Amiodarone treatment decreased metabolic clearance rates significantly from 0.107 +/- 0.008 in controls to 0.074 +/- 0.009 l/day in amiodarone-treated rabbits (p less than 0.05). However, when expressed per unit body weight (1.day-1.kg-1), the metabolic clearance rates were not significantly different between the controls and amiodarone-treated rabbits. The terminal serum elimination half-life in the two groups were similar (32.0 +/- 6.7 h in controls vs 49.2 +/- 12.4 h in amiodarone-treated).(ABSTRACT TRUNCATED AT 250 WORDS)