Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract.
To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon.
The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters Cmax, Tmax after the capsule activation, AUC0–24, and mean residence time were determined from the concentration–time profiles.
Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC0–24 values revealed some site-specific absorption tendencies, the mean AUC0–24 values obtained were similar regardless of the location of tacrolimus release from the capsule.
Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC0–24, possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Clinical Therapeutics
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- First clinical experience with a new once-daily formulation of tacrolimus.Ther Drug Monit. 2008; 30: 159-166
- A systematic review of the associations between dose regimens and medication compliance.Clin Ther. 2001; 23: 1296-1310
- Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation.J Am Soc Nephrol. 2005; 16: 1839-1848
- Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan.J Manag Care Pharm. 2008; 14: 291-301
- The role of gamma-scintigraphy in oral drug delivery.Adv Drug Deliv Rev. 2001; 46: 103-124
- Development of a new engineering-based capsule for human drug absorption studies.Pharm Sci Technol Today. 2000; 3: 385-392
- Evaluation of the Intelisite capsule to deliver theophylline and frusemide tablets to the small intestine and colon.Eur J Pharm Sci. 2001; 13: 375-384
- Assessment of lumiracoxib bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy.Pharm Res. 2004; 21: 443-446
- Use of the InteliSite capsule to study ranitidine absorption from various sites within the human intestinal tract.Pharm Res. 1998; 15: 1869-1875
- Comparison of tacrolimus (FK506) levels determined by three different methods in the rat blood.Drug Metab Pharmacokinet. 1995; 10: 837-847
- Transit of pharmaceutical dosage forms through the small intestine.Gut. 1986; 27: 886-892
- Gastric emptying of solids in man.Gut. 1982; 23: 292-296
- Variation in gastrointestinal transit of pharmaceutical dosage forms in healthy subjects.Pharm Res. 1991; 8: 360-364
- The hungry stomach: physiology, disease, and drug development opportunities.Front Pharmacol. 2010; 1: 145
- Gastric emptying of nondigestible solids in the fasted dog.J Pharm Sci. 1987; 76: 117-122
- Effects of gender, posture, and age on gastric residence time of an indigestible solid: pharmaceutical considerations.Pharm Res. 1988; 5: 639-644
- Drug delivery to the proximal colon.J Pharm Pharmacol. 1985; 37: 874-877
- Analysis and prediction of absorption behavior for theophylline orally administered as powders based on gastrointestinal-transit-absorption (Gita) model.Drug Metab Pharmacokinet. 2002; 17: 307-315
- Transit of a meal through the stomach, small intestine, and colon in normal subjects and its role in the pathogenesis of diarrhea.Gastroenterology. 1980; 79: 1276-1282
- The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups.Clin Pharmacol Ther. 2001; 69: 24-31
- Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects.J Clin Pharmacol. 2001; 41: 176-182
- Pharmacokinetics of FK506 following oral administration: a comparison of FK506 and cyclosporine.Transplant Proc. 1991; 23: 931-933
- The effect of gut metabolism on tacrolimus bioavailability in renal transplant recipients.Transplantation. 2001; 71: 1303-1307
- Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients.Pharmacogent Genom. 2006; 16: 119-127
- Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract.Br J Clin Pharmacol. 2005; 60: 54-60
- Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.J Pharmacol Exp Ther. 1997; 283: 1552-1562
- Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.Gut. 1995; 36: 259-267
- A higher dose requirement of tacrolimus in active Crohnʼs disease may be related to a high intestinal P-glycoprotein content.Diges Dis Sci. 2005; 50: 2312-2315
- Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients.J Am Soc Nephrol. 2003; 14: 1889-1896
- Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test.Drug Metab Dispos. 1994; 22: 947-955
- Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.J Pharmacol Exp Ther. 1994; 270: 414-423
- P-glycoprotein increases from proximal to distal regions of human small intestine.Pharm Res. 2003; 20: 1595-1599
- Effect of variations in the amounts of P-glycoprotein(ABCB1), BCRP (ABCG2) and CYP3A4 along the human small intestine on PBPK models for predicting intestinal first pass.Mol Pharm. 2010; 7: 1596-1607
Published online: March 27, 2014
Accepted: February 25, 2014
© 2014 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.