Pharmacokinetics of L-thyroxine after its oral administration in dogs

R. F. Nachreiner From the Animal Health Diagnostic Laboratory (Nachreiner, Refsal), and the Departments of Physiology and Large Animal Clinical Sciences (Nachreiner), Small Animal Clinical Sciences (Refsal, Hauptman, Rosser), Michigan State University, East Lansing, MI 48824, and the Departments of Physiology and Pharmacology (Pedersoli) and Pharmacal Sciences (Ravis), Auburn University, AL 36830.

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K. R. Refsal From the Animal Health Diagnostic Laboratory (Nachreiner, Refsal), and the Departments of Physiology and Large Animal Clinical Sciences (Nachreiner), Small Animal Clinical Sciences (Refsal, Hauptman, Rosser), Michigan State University, East Lansing, MI 48824, and the Departments of Physiology and Pharmacology (Pedersoli) and Pharmacal Sciences (Ravis), Auburn University, AL 36830.

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W. R. Ravis From the Animal Health Diagnostic Laboratory (Nachreiner, Refsal), and the Departments of Physiology and Large Animal Clinical Sciences (Nachreiner), Small Animal Clinical Sciences (Refsal, Hauptman, Rosser), Michigan State University, East Lansing, MI 48824, and the Departments of Physiology and Pharmacology (Pedersoli) and Pharmacal Sciences (Ravis), Auburn University, AL 36830.

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J. Hauptman From the Animal Health Diagnostic Laboratory (Nachreiner, Refsal), and the Departments of Physiology and Large Animal Clinical Sciences (Nachreiner), Small Animal Clinical Sciences (Refsal, Hauptman, Rosser), Michigan State University, East Lansing, MI 48824, and the Departments of Physiology and Pharmacology (Pedersoli) and Pharmacal Sciences (Ravis), Auburn University, AL 36830.

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E. J. Rosser From the Animal Health Diagnostic Laboratory (Nachreiner, Refsal), and the Departments of Physiology and Large Animal Clinical Sciences (Nachreiner), Small Animal Clinical Sciences (Refsal, Hauptman, Rosser), Michigan State University, East Lansing, MI 48824, and the Departments of Physiology and Pharmacology (Pedersoli) and Pharmacal Sciences (Ravis), Auburn University, AL 36830.

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W. M. Pedersoli From the Animal Health Diagnostic Laboratory (Nachreiner, Refsal), and the Departments of Physiology and Large Animal Clinical Sciences (Nachreiner), Small Animal Clinical Sciences (Refsal, Hauptman, Rosser), Michigan State University, East Lansing, MI 48824, and the Departments of Physiology and Pharmacology (Pedersoli) and Pharmacal Sciences (Ravis), Auburn University, AL 36830.

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Summary

Twelve mature (5 sexually intact males, 4 castrated males, and 3 females) mixed-breed dogs were surgically thyroidectomized and used in a Latin-square design pharmacokinetic study of orally administered l-thyroxine. The dogs were treated with 44, 22, and 11 μg of l-thyroxine/kg as a single morning dose or in divided doses, morning and evening. Serum concentration of thyroxine (T4) was evaluated to determine a number of pharmacokinetic variables for comparison. Mean steady-state concentrations (Css) were determined from the area under the curve. Variables were analyzed for comparisons between dosages by use of anova.

Concentration at steady state was highest for dogs of the 44-μg/kg of body weight once-daily group and was lowest for dogs of the group given 11 μg/kg in 2 daily doses. Single daily administration resulted in higher Css, except at the 22-μg/kg/d dosage. Clearance was faster for the 22- and 44-μg/kg/d dosages than for the 11-μg/kg/d dosage. The half-life (t1/2) and mean residence time (mrt) also were shorter for the 44-μg/kg/d dosage, possibly indicating more rapid elimination of the drug at higher doses and dose-dependent kinetics. Perhaps, as the dogs’ metabolism increased with higher iodothyronine concentrations, hormone degradation was accelerated. Interval (divided vs single dose) caused some expected changes: maximal concentration was higher and minimal concentration was lower when single administration was used. These undulations resulted in iodothyronine concentrations above the physiologic range for a number of hours, whereas concentration closer to physiologic ranges was achieved by use of divided doses. Delayed absorption (lag time) was seen in 37 of the 72 data sets, but was generally short, about 0.25 hour. Mean time to maximal concentration was 3 to 4 hours. At the higher dosages, serum total T4 concentration was high normal or above normal during most of the time after l-thyroxine administration, but serum concentration of total 3,5,3′-triiodothyronine did not remain within the normal range until the 44-μg/kg/d dosage was used. The customary dosage of 22 μg/kg/d (0.1 mg/10 lb/d) may not be adequate for most dogs. Pharmacokinetic variables appear to be highly dependent on the individual dog. Those with rapid absorption and higher concentration tended to have these characteristics at each dosage in this study. The pharmacokinetic variables, therefore, appear to be highly individualized, and dosages recommended for treatment of hypothyroidism should be considered to be only a starting point for the average dog. To avoid underdosing or overdosing, monitoring of treatment to adjust dose for individual dog kinetic variables seems to be imperative.

Summary

Twelve mature (5 sexually intact males, 4 castrated males, and 3 females) mixed-breed dogs were surgically thyroidectomized and used in a Latin-square design pharmacokinetic study of orally administered l-thyroxine. The dogs were treated with 44, 22, and 11 μg of l-thyroxine/kg as a single morning dose or in divided doses, morning and evening. Serum concentration of thyroxine (T4) was evaluated to determine a number of pharmacokinetic variables for comparison. Mean steady-state concentrations (Css) were determined from the area under the curve. Variables were analyzed for comparisons between dosages by use of anova.

Concentration at steady state was highest for dogs of the 44-μg/kg of body weight once-daily group and was lowest for dogs of the group given 11 μg/kg in 2 daily doses. Single daily administration resulted in higher Css, except at the 22-μg/kg/d dosage. Clearance was faster for the 22- and 44-μg/kg/d dosages than for the 11-μg/kg/d dosage. The half-life (t1/2) and mean residence time (mrt) also were shorter for the 44-μg/kg/d dosage, possibly indicating more rapid elimination of the drug at higher doses and dose-dependent kinetics. Perhaps, as the dogs’ metabolism increased with higher iodothyronine concentrations, hormone degradation was accelerated. Interval (divided vs single dose) caused some expected changes: maximal concentration was higher and minimal concentration was lower when single administration was used. These undulations resulted in iodothyronine concentrations above the physiologic range for a number of hours, whereas concentration closer to physiologic ranges was achieved by use of divided doses. Delayed absorption (lag time) was seen in 37 of the 72 data sets, but was generally short, about 0.25 hour. Mean time to maximal concentration was 3 to 4 hours. At the higher dosages, serum total T4 concentration was high normal or above normal during most of the time after l-thyroxine administration, but serum concentration of total 3,5,3′-triiodothyronine did not remain within the normal range until the 44-μg/kg/d dosage was used. The customary dosage of 22 μg/kg/d (0.1 mg/10 lb/d) may not be adequate for most dogs. Pharmacokinetic variables appear to be highly dependent on the individual dog. Those with rapid absorption and higher concentration tended to have these characteristics at each dosage in this study. The pharmacokinetic variables, therefore, appear to be highly individualized, and dosages recommended for treatment of hypothyroidism should be considered to be only a starting point for the average dog. To avoid underdosing or overdosing, monitoring of treatment to adjust dose for individual dog kinetic variables seems to be imperative.

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