Conjugated metabolites of ritodrine

• Main Author: Brashear, Wayne T
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-1989
• Subjects: Pharmacology
• ISBN: 9798207434346

Ritodrine is a $\beta$-2-adrenergic agonist which is used clinically for the management of preterm labor. The $\beta$-2 activity of ritodrine produces relaxation of the smooth muscles of the uterus and is believed to act directly on the $\beta$-2 receptors of the myometrium. Since ritodrine is resistant towards the action of monoamine oxidase and catecholamine-O-methyl transferase, conjugation is an important route of metabolism. Previous studies have indicated that ritodrine is metabolized by sulfate and glucuronide conjugation. However, the relative amounts of these conjugates were not measured. The purpose of this dissertation is to measure the relative amounts of the conjugates and to determine their chemical structure. The urinary conjugates of ritodrine were characterized in a study of seven maternal-neonatal pairs. The study population consisted of mothers who went on to deliver infants despite ritodrine therapy. Investigations of the maternal and neonatal urinary excretion of ritodrine indicate that 80-90% of the drug is in the form of conjugated metabolites. The sulfate conjugate accounts for 45% of maternal excretion and 66% of neonatal excretion; the glucuronide conjugate accounts for 38% and 23% of maternal and neonatal excretion, respectively. Significantly different metabolic profiles suggest that the neonate may be capable of forming conjugated metabolites of ritodrine. The structure of the conjugates of ritodrine was determined from the urinary metabolites of ritodrine patients. Maternal urine was purified by ion-exchange chromatography. The partially purified metabolites were permethylated using methyl iodide in hexamethylphosphoramide. Volatile derivatives of the glucuronide and sulfate conjugates were analyzed by combined gas chromatography/mass spectrometry. These data did not indicate an exclusive site of conjugation. Analysis of both the sulfate and glucuronide conjugates indicated that either of ritodrine's two phenolic hydroxyl groups may be involved in the formation of conjugated metabolites. However, conjugation of the (2-(p-hydroxyphenyl)-2-hydroxy-1-methylethyl) amine phenolic hydroxyl group is unique, since it is located on the portion of the ritodrine molecule which more closely resembles the structure of endogenous catecholamines. This is consistent with the structural determinations of other $\beta$-adrenergic agonists which have shown that phenolic hydroxyl groups are frequent sites of conjugation.