title: 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 characterized 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 whether 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 50 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 (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, 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 h after 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 more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas 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.
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
authors.forename: Dirk R J
authors.initials: DR
authors.lastname: Kuypers
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
authors.forename: P
authors.initials: P
authors.lastname: Evenepoel
authors.forename: B
authors.initials: B
authors.lastname: Maes
authors.forename: Yves
authors.initials: Y
authors.lastname: Vanrenterghem
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001944:Breath Tests; D002210:Caprylates / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000502:physiology*; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D002210:Caprylates; D007166:Immunosuppressive Agents; C031492:octanoic acid; D016559:Tacrolimus