Long-term Levothyroxine Treatment Decreases the Oral Bioavailability of Cyclosporin A by Inducing P-glycoprotein in Small Intestine

Abstract

Summary:We have noticed that the trough level of blood concentration of cyclosporin A (CyA) tends to be lower in patients receiving long-term oral levothyroxine (LTX) than in patients not receiving LTX. We conˆrmed this clinical observation in experiments using Wistar rats orally given LTX (8 mg W kg) or saline (control) for 3 weeks, followed by CyA (10 mg W kg). The LTX treatment had little eŠect on the blood concentrations of CyA after i.v. administration, whereas they were decreased signiˆcantly after p.o. administration. After p.o. administration, the value of the area under the blood concentration-time curve from 0 to 24 hr and the bioavailability of CyA in the LTX group were decreased to only about onefth and a quarter of those in the control group, respectively. After treatment with LTX, the expression levels of mdr1a, mdr1b and CYP3A2 mRNAs in the duodenum were markedly increased to about twice the control, but in jejunum, ileum and liver the expression levels were little changed. Theseˆndings suggest that the absorption of CyA, which occurs mainly from the upper intestine, is reduced as a result of eOEux transport via P-glycoprotein induced by LTX. In conclusion, careful monitoring of CyA levels is required in the event of LTX administration to patients receiving immunotherapy with CyA.

Beyond Cyclosporine A: Conformation-Dependent Passive Membrane Permeabilities of Cyclic Peptide Natural Products

“…An archetypal example is the natural product cyclosporine A (CSA), a cyclic undecapeptide immunosuppressant that is passively permeable and has an oral bioavailability of 29% [22]. While many other cyclic peptide natural products have structures that also suggest bioavailability [21], there have been no reports that systematically examine the passive membrane permeabilities of other naturally occurring cyclic peptides.…”

Linezolid Underexposure in a Hypothyroid Patient on Levothyroxine Replacement Therapy

“…8 Significant decrease of oral bioavailability of cyclosporine A, by P-gp induction in intestine, was observed in an experimental rat model during levothyroxine cotreatment. 12 This mechanism was considered responsible for the significantly lower cyclosporine C min observed among 10 patients who were on long-term cotreatment with cyclosporine and 100 mcg daily oral levothyroxine, as compared with values from 30 patients who took only cyclosporine. 12 Overall, these data suggest that the long-term levothyroxine replacement therapy might have increased CL/F of linezolid in our hypothyroid patient.…”

“…12 This mechanism was considered responsible for the significantly lower cyclosporine C min observed among 10 patients who were on long-term cotreatment with cyclosporine and 100 mcg daily oral levothyroxine, as compared with values from 30 patients who took only cyclosporine. 12 Overall, these data suggest that the long-term levothyroxine replacement therapy might have increased CL/F of linezolid in our hypothyroid patient. Clinicians should be aware that patients who receive standard oral dosages of linezolid while on replacement therapy with levothyroxine might experience linezolid underexposure and that TDM may be valuable in these occasions.…”

Thyroid Hormone Regulates the Expression and Function of P-glycoprotein in Caco-2 Cells

“…Therefore, it is likely that the kinetics of diazepam are not affected with hyperthyroidism. As for Pgp substrates, it was recently reported that long-term levothyroxine treatment decreased the oral bioavailability of cyclosporine A (29). Thus, it is reasonable to assume that the changes in Pgp expression in the human gut affect at least in part the alteration of the blood concentration of digoxin.…”