Evaluation of the Role of P-glycoprotein (P-gp)-Mediated Efflux in the Intestinal Absorption of Common Substrates with Elacridar, a P-gp Inhibitor, in Rats
Background and Objectives P-glycoprotein (P-gp) has been shown previously to contribute to the intestinal absorption of verapamil, diltiazem, tacrolimus, colchicine and indinavir in situ; however, its contribution in vivo is unknown. The present study aimed to evaluate the in vivo involvement of P-g...
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Veröffentlicht in: | European journal of drug metabolism and pharmacokinetics 2020-06, Vol.45 (3), p.385-392 |
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Sprache: | eng |
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Zusammenfassung: | Background and Objectives
P-glycoprotein (P-gp) has been shown previously to contribute to the intestinal absorption of verapamil, diltiazem, tacrolimus, colchicine and indinavir in situ; however, its contribution in vivo is unknown. The present study aimed to evaluate the in vivo involvement of P-gp using elacridar as its inhibitor to distinguish the contribution of P-gp from cytochrome P450 (CYP) 3A.
Methods
Fexofenadine (5 mg/kg) and buspirone (1 mg/kg) were used as probe substrates of P-gp and CYP3A, respectively. Each dual substrate (1 or 2 mg/kg) was orally administered to rats after elacridar pre-treatment (3 mg/kg). Additionally, verapamil, diltiazem or tacrolimus was orally co-administered with fexofenadine.
Results
Elacridar drastically increased the area under the plasma concentration–time curve (AUC
0–
t
) of oral fexofenadine by 8.6-fold; however, it did not affect the AUC
0–
t
of oral buspirone. Therefore, elacridar inhibited P-gp without affecting CYP3A. The absorption of oral verapamil, diltiazem and tacrolimus was not influenced by elacridar pre-treatment, and the increase in the AUC
0–
t
of fexofenadine was approximately 3-fold when co-administered with each substrate; the minimal effect of elacridar was attributable to the limited contribution of P-gp but not to their self-inhibition against the transporter. Conversely, elacridar significantly increased the AUC
0–
t
of colchicine (5.3-fold) and indinavir (2.0-fold), indicating that P-gp contributes to their absorption.
Conclusions
Elacridar is useful for distinguishing the contribution of P-gp from CYP3A to the absorption of drugs in rats. The in vivo contribution of P-gp is minimal for high permeable compounds owing to their fraction absorbed of nearly 1.0. |
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ISSN: | 0378-7966 2107-0180 |
DOI: | 10.1007/s13318-019-00602-7 |