Pharmacokinetic evaluation in man of terbutaline given as separate enantiomers and as the racemate.

Abstract

1. The pharmacokinetics of the two enantiomers of terbutaline, (+)T and (‐)T, and the racemate (+/‐)T, have been evaluated after single intravenous and oral dosage to six healthy volunteers. 2. The mean systemic clearance, CL, was 0.19 and 0.13 l h‐1 kg‐1 for (+)T and (‐)T, respectively. This difference was statistically significant. The mean clearance of (+/‐)T was 0.20 l h‐1 kg‐1. Volumes of distribution were similar (1.9 l kg‐1) after the three intravenous administrations. The differences in CL were reflected in values of the elimination half‐life and MRT. 3. The difference in CL of the isomers could be explained by a corresponding difference in their renal clearance, CLR. Competition for stereoselective active reabsorption in the tubule might explain why (+)T seemed to enhance the CLR of (‐)T when the drug was given as the racemate. 4. Oral bioavailability, calculated from plasma data, of (+)T was 7.5% and that of (‐)T was 14.8%. This difference was statistically significant and was mainly due to a difference in absorption of (+)T and (‐)T, but also to a difference in their subsequent first‐pass metabolism. The bioavailability of (+/‐)T was similar to that of (‐)T. 5. (‐)T appears to govern the absorption properties of the racemate, while (+)T determines its elimination behaviour. Systemic metabolism of the two enantiomers was similar and, therefore, a greater first‐pass metabolism of (+)T would reflect a higher capacity of the gut wall to metabolise this isomer.

Prediction of human pharmacokinetics—gut-wall metabolism

“…The first-pass E GW for other CYP3A4-substates, ciclosporin, methadone and verapamil, are estimated to be 0.4-0.6 (depending on estimate used for CL H ), 0.22 and 0.49, respectively (von Richter et al 2001; Wacher et al 2001;Kharasch et al 2004). Salbutamol and terbutaline, which are primarily metabolized to sulfate conjugates, also have high first-pass E GW, and this is also the case for the UGT1A1 probe ethynylestradiol (Borgström et al 1989;Mizuma et al 2005). Based on a f a value from the GI tract of 0.60, oral F of 0.14, hepatic plasma flow rate of 700 mL min −1 and metabolic plasma CL of 82 mL min −1 (Borgström et al 1989), the first-pass E GW and E H of terbutaline are estimated to be 0.74 and 0.12, respectively.…”

“…Salbutamol and terbutaline, which are primarily metabolized to sulfate conjugates, also have high first-pass E GW, and this is also the case for the UGT1A1 probe ethynylestradiol (Borgström et al 1989;Mizuma et al 2005). Based on a f a value from the GI tract of 0.60, oral F of 0.14, hepatic plasma flow rate of 700 mL min −1 and metabolic plasma CL of 82 mL min −1 (Borgström et al 1989), the first-pass E GW and E H of terbutaline are estimated to be 0.74 and 0.12, respectively. As shown above, gut-wall contents of other CYP450s are generally lower than for CYP3A4.…”

“…If such a hypothesis holds, we could expect low P e compounds (which are to a greater extent absorbed from regions with lower enzymatic activity-small intestinal villi crypts and colon) to have comparably lower first-pass E GW . Despite low/moderate GI P e and fraction absorbed (f a ) (Borgström et al 1989), the highly hydrophilic terbutaline has a high first-pass E GW (approximated to 0.74; see below). The high E GW suggests that this compound is not absorbed from the villi crypts to any significant extent (opposite of the suggested hypothesis), or that it is absorbed to some extent by crypts by cells with high sulfation capacity.…”

Stability indicating HPTLC method for determination of terbutaline Sulfate in bulk and from Submicronized dry Powder inhalers

“…According to some researchers, derivatization has an important role in the detection of TBS, 31 usually trimethylsilylation is the standard procedure for this purpose. [24][25][26][27] However to our knowledge, there has been no work reported in the literature about the highperformance thin-layer chromatographic (HPTLC) analysis of TBS in either biological fluids or pharmaceutical formulations. HPTLC has advantages over other methods because of rapidity, selectivity, economy and overall versatility in QC aspects of drugs.…”

“…24 For TBS pharmacokinetic studies, the most useful analytical method is GC-mass spectrometry. 2,25,26 Isolation of unchanged compounds and metabolites from biological samples by GC-MS necessitates elimination of matrix interferences by liquid-liquid extraction, 27 solid phase extraction 28,29 or both. 24 Recently, electrospray high-field asymmetric waveform ion mobility spectrometry-mass spectrometry (ESI-FAIMS-MS) 30 has been reported as a new approach to chiral separation of TBS enantiomers.…”