Received for publication July 20, 2004.
Revised September 15, 2004.
Accepted for publication September 15, 2004.

The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients

Abstract

Tacrolimus is characterised by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed if the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in fifty renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by Area-Under-the-Concentration-time-Curve sampling. Gastric half emptying time (t 1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r²=0.30; p<0.0001) while the gastric emptying coefficient (GEC), reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r²=0.14; p=0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 hours following oral drug administration (r²=0.96; p<0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly slower in the former group (tmax: 2 ± 1 hr vs. 1.48 ± 0.68 hr; p=0.04) while the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.

Key words: absorption, bioavailability, clinical pharmacokinetics, human pharmacokinetics, immunosuppression