Pharmacokinetics and Excretion of the Novel Anti-tuberculosis Compound 1,2:5,6-Di-O-isopropylidene-3-O-(phenyl cyclopropyl methanonyl)-α-D-glucofuranose (S-001-14) after Oral Doses in Rats

Jawahar Lal; Rama Pati Tripathi; Ram Chandra Gupta

doi:10.1055/s-0031-1296529

Arzneimittelforschung, Inhaltsverzeichnis

Arzneimittelforschung 2008; 58(08): 410-418
DOI: 10.1055/s-0031-1296529

Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics

Editio Cantor Verlag Aulendorf (Germany)

Pharmacokinetics and Excretion of the Novel Anti-tuberculosis Compound 1,2:5,6-Di-O-isopropylidene-3-O-(phenyl cyclopropyl methanonyl)-α-D-glucofuranose (S-001-14) after Oral Doses in Rats

Development of a sensitive and reproducible high performance liquid chromatography-UV method for the determination of the test compound in rat serum

Jawahar Lal

¹Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India

,

Rama Pati Tripathi

²Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India

,

Ram Chandra Gupta

¹Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India

› Institutsangaben

Abstract

A sensitive and reproducible high performance liquid chromatography (HPLC)-UV method for the determination of the novel anti-tuberculosis compound l,2:5,6-di-o-isopropylidene-3-O-(phenyl cyclopropyl methanonyl)-α-D-glucofuranose (S-001-14) has been developed and validated in rat serum, urine and feces. Following extraction with hexane at alkaline pH, samples were separated on a reverse phase C18 column and quantified using UV detection at 267 nm. The mobile phase was 70% acetonitrile in ammonium acetate buffer (10 mmol/L, pH 6.0) with a flow rate of 1.0 ml/min. The method was used to determine the pharmacokinetics and excretion of S-001-14 after oral doses in rats. Linearity was satisfactory over the concentration range of 5 – 500 ng/ml (r², >0.99). Recoveries were >90% and were consistent throughout the calibration range. The precision and accuracy were acceptable as indicated by relative standard deviation ranging from 2.72 to 9.54%, bias values ranging from 1.62 to 12.05%. Moreover, S-001-14 was stable in rat serum after being subjected to three freeze-thaw cycles and for 30 days on storage at −60 °C. The method was used to determine the serum concentration-time profiles for S-001-14 after oral doses of 4,100 and 200 mg/kg in rats. A linear pharmacokinetics was found in rats at 100 and 200 mg/kg doses with a long elimination half-life (~24 h), wide distribution and bioavailability of ~13%. The excretion study after the 100 mg/kg oral dose revealed that S-001-14 was excreted in urine (0.002 ± 0.001%) and feces (15.6 ± 3.5%).

Key words

Anti-tuberculosis agents - Phenyl cyclopropyl methanones - S-001-14, HPLC, pharmacokinetics, rat

Volltext

Referenzen

References
1 World Health Organization (WHO). Tuberculosis Facts – Handout 2007, Retrieved on 1 June 2007.
2 Grover RK, Mishra RC, Verma SS, Tripathi RP, Roy R, Srivastava R et al. Novel phenyl cyclopropyl methanones useful as Antitubercular agents. Indian Patent Application No. 0363/DEL/2004.
3 Hartman C, Penninckx W, Heyden YV, Vankeerberghen P, Massart DL, McDowall RD. Experience with chromatographic methods – Europe. In: Blume HH, Midha KK. (editors) Bio’94, Bio-international 2, Bioavailability, Bioequiva-lence and Pharmacokinetic Studies. Stuttgart (Germany): Medpharm Scientific; 1995. pp. 336-588
4 Shah VP, Midha KK, Findlay JWA, Hill HM, Hulse JD, Mcgilvery IJ et al. Bioanalytical method validation-a revisit with a decade of progress. Pharm Res. 2000; 17: 1551-1557
5 Said A, Makki S, Muret P, Rouland JC, Tubin G, Millet J. Lipophilicity determination of psoralens used in therapy through solubility and partitioning: comparison of theoretical and experimental approaches. J Pharm Sci. 1996; 85: 387-392
6 WinNonlin (Version 1.5), SCI Software, Lexington, KY.
7 Oberle RL, Amidon GL. The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of Cimetidine: an explanation for the double peak phenomenon. J Pharmacol Biopharm. 1987; 15: 529-544
8 Garg DC, Weidler DJ, Eshelman FN. Ranitidine bioavailability and kinetics in normal male subject. Clin Pharmacokinet. 1983; 33: 445-452
9 Hammarlund MM, Paalzow LK, Odlind B. Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis. Eur J Clin Pharmacol. 1984; 26: 197-207
10 Bergstrom RF, Kay DR, Harkcom TM, Wagner JG. Penicillamine kinetics in normal subjects. Clin Pharmacol Ther. 1981; 30: 404-413
11 Piquette-Miller M, Jamali F. Pharmacokinetics and multiple peaking of acebutolol enantiomers in rats. Biopharm Drug Dispos. 1977; 18: 543-556
12 Plusquellec Y, Campistron G, Staveris S, Barre J, Jung L, Tillement JP et al. A double peak phenomenon in the pharmacokinetics of veralipride after oral administration: a double-site model for drug absorption. J Pharmacokin Biopharm. 1987; 15: 225-239
13 Wang Y, Roy A, Sun L, Lau CE. A double peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab Dispos. 1999; 27: 855-859
14 Imbimbo BP, Daniotti S, Vidi A, Foschi D, Saporiti F, Ferrante L. Discontinuous oral absorption of cimetroprium bromide, a new antispasmodic drug. J Pharm Sci. 1986; 75: 680-684
15 Houston JB, Upshall DG, Bridges JW. Further studies using carbamate esters as model compounds to investigate the role of lipophilicity in the gastrointestinal absorption of foreign compounds. J Pharmacol Exp Ther. 1975; 195: 67-92
16 Veng Pedersen P. Cimetidine bioavailability and second peak phenomenon. J Pharm Sci. 1981; 70: 32-38