Pharmacokinetics and pharmacodynamics of ritodrine hydrochloride administered orally and intramuscularly to female healthy volunteers

Abstract

Ritodrine hydrochloride ((R,S)–4-hydroxy-β-[1-[2-((4-hydroxyphenyl)ethyl]amino)ethyl]benzenemethanol, CAS 26652-09-5) is a direct-acting sympathomimetic agent with a predominant β-adrenergic activity and a selective action on β₂-receptors. A clinical trial was carried out to investigate the pharmacokinetics, pharmacodynamics and safety of ritodrine hydrochloride administered at the dose of 10, 20 and 30 mg p.o. and 10 mg by i.m. route. A four-way randomised crossover design was adopted on 12 health female volunteers with a wash-out of a least 14 days. Concentrations of ritodrine and of the pool of ritodrine in plasma and concentrations of the pool of ritodrine in urine of volunteers were bioassayed with tandem mass spectrometry. The following pharmacokinetic parameters wer calculated, using the non-compartmental model: C_max, AUC_0–t, AUC_0–INF, t_1/2, V_d/f, and Aet after each administration. The distribution volume of ritodrine proved to be about 3 times higher than that of the pool of ritodrine after i.m. injection confirming the good permeability of ritodrine that massively enters tissue compartments. Statistical analyses of phar-macokinetic parameters ascertained that the p.o. absorption of ritodrine hydro-chloride was linearly related with the doses administered in the 10–30 mg range. The pharmacodynamic parameters evaluated complied with the mechanism of action of this drug.

Key word

CAS 23239-51-2 - Ritodrine, i.m. absorption, pharmacodynamics, pharma-cokinetics, p.o. absorption - Sympathomimetic agent

• Reference

• 1 Ritodrine. In: Budavari S. editor. The Merck Index. 11th edition. Rahway (NJ, USA):: Merck and Co., Inc.; 1989: 1311
• 2 Volkert C, Dijk JV, Durk MH inventors; Philips Corp, as signee; Pharmaceutical composition containing 1-(4-hy droxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propa nol and salts thereof. United States patent US 3,410,944 1968 Nov 12.
• 3 Graves CR. Agents that cause contractions or relaxation of the uterus. In: JG Hardman, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A. editors. Goodman & Gil- man’s The pharmacological basis of therapeutics. 9^th edition. New York (NY, USA): The McGraw-Hill Company; 1996. p. 939-949
• 4 Ritodrine hydrochorlide. In: Sweetman SC, et al. editors. Martindale. The Complete Drug Reference. 35^th edition. London (UK): The Royal Pharmaceutical Society; 2007. p. 2158
• 5 Thomas K, Vankrieken L, VanLierde M. Characterization of ritodrine radio-immunoassay: standard curves, cross-reac tions and serum levels in women. Gynaecol Obstet Invest. 1982; 14: 151-55
• 6 vanLierde M, Thomas K. Ritodrine concentrations in maternal and fetal serum and amniotic fluid. J Perinatal Med. 1982; 10: 119-24
• 7 Gandar R, deZoeten LW, vander Schoot JB. Serum level of ritodrine in man. Eur J Clin Pharmacol. 1980; 17: 117-22
• 8 Wright MR, Axelson JE, Abbott FS, Riggs KW, VandeWeyde MP, Taylor SM et al. Determination of ritodrine in biological fluids of the pregnant sheep by fused-silica ca pillary gas chromatography using electron-capture detection. J Chromatog. 1991; 565: 225-36
• 9 Kuhnert P, Erhard P, Dixon A, Kuhnert B, Gross T. Deter mination of ritodrine in plasma using HPLC. J Liquid Chromatog. 1983; 6: 2775-83
• 10 Lin LS, Caritis SN, Wong LK. Analysis of ritodrine by highperformance liquid chromatography with electrochemical detection. J Pharm Sci. 1984; 73: 131-3
• 11 Marzo A, Dal Bo L. Tandem mass spectrometry (LC-MS-MS): a predominant role in bioassays for pharmacokinetic studies. Arzneimittelforschung. 2007; 57 (2) 122-8
• 12 Liu A, Liu F, Xu Y, Xu F, Hu W, Guo Q. Determination of ritodrine in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 867: 144-8
• 13 Ohmori T, Nakamura M, Tada S, Sugiyama T, Itoh Y, Udagawa Y et al. A highly sensitive assay for ritodrine in human serum by hydrophilic interaction chromatography-tandem mass spectrometry. J Chomatogr B Analyt Technol Biomed Life Sci. 2008; 861: 95-100
• 14 Note for guidance on the investigation of bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98; July 2001.
• 15 Caritis SN, Lin LS, Wong LK. Evaluation of the pharmaco-dynamics and pharmacokinetics of ritodrine when administered as a loading dose: on establishing a potentially useful drug administration regimen in case of fetal distress. Am J Obstet Gynecol. 1985; 152: 1026-31
• 16 Caritis SN, Venkataramanan R, Cotroneo M, Smith M, Chiao JP, Habucky K. Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women. Am J Obstet Gynecol. 1990; 162: 1215-9
• 17 Brashear WT, Kuhnert BR, Wei R. Maternal and neonatal urinary excretion of sulfate and glucuronide ritodrine conjugates. Clin Pharmacol Ther. 1988; 44: 634-41
• 18 Kuhnert BR, Gross TL, Kuhnert PM, Erhard P, Brashar WT. Ritodrine pharmacokinetics. Clin Pharmacol Ther. 1986; 40: 656-64