The Effect of Loperamide and Fentanyl on the Distribution Kinetics of Verapamil in the Lung and Brain in Sprague Dawley Rats
Verapamil has been shown to inhibit fentanyl uptake in vitro and is a potent P-glycoprotein inhibitor. Tissue partitioning of loperamide, a commercially available opioid, is closely controlled by the P-gp efflux transporter. The following studies were designed to evaluate the effect of opioids on verapamil partitioning in the lung and brain, in vivo. Opioid (fentanyl or loperamide) was administered by intravenous infusion to Sprague Dawley rats alone or in combination with verapamil and plasma, with lung and brain tissues were collected at 1, 5, 6, 8, 10 and 60 minutes. Drug dispositions were modeled by recirculatory pharmacokinetic models. Fentanyl slightly increased the verapamil lung (PL) partition coefficient yet decreased the brain (PB) partition coefficient. Furthermore, loperamide significantly increased PLand PB. Fentanyl reduced the verapamil volume of distribution (V1) and verapamil elimination clearance (ClE). Fentanyl decreased verapamil brain partitioning, yet increased verapamil lung partitioning. Also, loperamide increased lung and brain partitioning in vivo. These results suggest that verapamil and fentanyl may be substrates of an unidentified inward transporter in brain tissue and confirm that verapamil and loperamide are substrates of the efflux transporter P-gp.
[1] Roerig DL, Kotrly KJ, Dawson CA, Ahlf SB, Gualtieri JF, Kampine JP:
First-pass uptake of verapamil, diazepam, and thiopental in the human
lung. Anesthesia & Analgesia 1989; 69: 461-6.
[2] Roerig DL, Kotrly KJ, Vucins EJ, Ahlf SB, Dawson CA, Kampine JP:
First pass uptake of fentanyl, meperidine, and morphine in the human lung. Anesthesiology 1987; 67: 466-72.
[3] Taeger K, Weninger E, Schmelzer F, Adt M, Franke N, Peter K: Pulmonary kinetics of fentanyl and alfentanil in surgical patients. British
Journal of Anaesthesia 1988; 61: 425-34.
[4] Waters CM, Krejcie TC, Avram MJ: Facilitated uptake of fentanyl, but
not alfentanil, by human pulmonary endothelial cells. Anesthesiology 2000; 93: 825-31.
[5] Henthorn TK, Krejcie TC, Avram MJ, Jensen TR, Waters CM: Transporter-mediated pulmonary endothelial uptake of fentanyl. International Journal of Clinical Pharmacology & Therapeutics 1998;
36: 74-5.
[6] Waters CM, Avram MJ, Krejcie TC, Henthorn TK: Uptake of fentanyl
in pulmonary endothelium. Journal of Pharmacology & Experimental Therapeutics 1999; 288: 157-63.
[7] Henthorn TK, Liu Y, Mahapatro M, Ng KY: Active transport of fentanyl
by the blood-brain barrier. Journal of Pharmacology & Experimental Therapeutics 1999; 289: 1084-9.
[8] Bhatti MM, Foster RT: Pharmacokinetics of the enantiomers of
verapamil after intravenous and oral administration of racemic
verapamil in a rat model. Biopharmaceutics & Drug Disposition 1997; 18: 387-96.
[9] Gustafsson LL, Ebling WF, Osaki E, Harapat S, Stanski DR, Shafer SL:
Plasma concentration clamping in the rat using a computer-controlled
infusion pump. Pharmaceutical Research 1992; 9: 800-7.
[10] Ludden TM, Beal SL, Sheiner LB: Comparison of the Akaike
Information Criterion, the Schwarz criterion and the F test as guides to
model selection. Journal of Pharmacokinetics & Biopharmaceutics 1994;
22: 431-45.
[11] Hagenbuch B, Meier PJ: The superfamily of organic anion transporting
polypeptides. Biochimica et Biophysica Acta 2003; 1609: 1-18.
[12] Gao B, Stieger B, Noe B, Fritschy JM, Meier PJ: Localization of the
organic anion transporting polypeptide 2 (Oatp2) in capillary
endothelium and choroid plexus epithelium of rat brain. Journal of
Histochemistry & Cytochemistry 1999; 47: 1255-64.
[13] Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB: OATP and
P-glycoprotein transporters mediate the cellular uptake and excretion of
fexofenadine. Drug Metabolism & Disposition 1999; 27: 866-71.
[14] Schinkel AH, Wagenaar E, Mol CA, van Deemter L: P-glycoprotein in
the blood-brain barrier of mice influences the brain penetration and
pharmacological activity of many drugs. Journal of Clinical
Investigation 1996; 97: 2517-24.
[15] Dagenais C, Graff CL, Pollack GM: Variable modulation of opioid brain
uptake by P-glycoprotein in mice. Biochemical Pharmacology 2004; 67:
269-76.
[16] Ayrton A, Morgan P: Role of transport proteins in drug absorption,
distribution and excretion. Xenobiotica 2001; 31: 469-97.
[17] Verschraagen M, Koks CH, Schellens JH, Beijnen JH: P-glycoprotein
system as a determinant of drug interactions: the case of digoxinverapamil.
Pharmacological Research 1999; 40: 301-6.
[18] Iman A Elkiweri, Yan Ling Zhang, Uwe Christians, Ka-Yun Ng,
Martha C Tissot van Patot, Thomas K Henthorn : Competitive substrates
for P-glycoprotein and organic anion protein transporters differentially
reduce blood organ transport of fentanyl and loperamide:
pharmacokinetics and pharmacodynamics in Sprague-Dawley rats.
Anesth Analg.2009; 108: 149-159.
[1] Roerig DL, Kotrly KJ, Dawson CA, Ahlf SB, Gualtieri JF, Kampine JP:
First-pass uptake of verapamil, diazepam, and thiopental in the human
lung. Anesthesia & Analgesia 1989; 69: 461-6.
[2] Roerig DL, Kotrly KJ, Vucins EJ, Ahlf SB, Dawson CA, Kampine JP:
First pass uptake of fentanyl, meperidine, and morphine in the human lung. Anesthesiology 1987; 67: 466-72.
[3] Taeger K, Weninger E, Schmelzer F, Adt M, Franke N, Peter K: Pulmonary kinetics of fentanyl and alfentanil in surgical patients. British
Journal of Anaesthesia 1988; 61: 425-34.
[4] Waters CM, Krejcie TC, Avram MJ: Facilitated uptake of fentanyl, but
not alfentanil, by human pulmonary endothelial cells. Anesthesiology 2000; 93: 825-31.
[5] Henthorn TK, Krejcie TC, Avram MJ, Jensen TR, Waters CM: Transporter-mediated pulmonary endothelial uptake of fentanyl. International Journal of Clinical Pharmacology & Therapeutics 1998;
36: 74-5.
[6] Waters CM, Avram MJ, Krejcie TC, Henthorn TK: Uptake of fentanyl
in pulmonary endothelium. Journal of Pharmacology & Experimental Therapeutics 1999; 288: 157-63.
[7] Henthorn TK, Liu Y, Mahapatro M, Ng KY: Active transport of fentanyl
by the blood-brain barrier. Journal of Pharmacology & Experimental Therapeutics 1999; 289: 1084-9.
[8] Bhatti MM, Foster RT: Pharmacokinetics of the enantiomers of
verapamil after intravenous and oral administration of racemic
verapamil in a rat model. Biopharmaceutics & Drug Disposition 1997; 18: 387-96.
[9] Gustafsson LL, Ebling WF, Osaki E, Harapat S, Stanski DR, Shafer SL:
Plasma concentration clamping in the rat using a computer-controlled
infusion pump. Pharmaceutical Research 1992; 9: 800-7.
[10] Ludden TM, Beal SL, Sheiner LB: Comparison of the Akaike
Information Criterion, the Schwarz criterion and the F test as guides to
model selection. Journal of Pharmacokinetics & Biopharmaceutics 1994;
22: 431-45.
[11] Hagenbuch B, Meier PJ: The superfamily of organic anion transporting
polypeptides. Biochimica et Biophysica Acta 2003; 1609: 1-18.
[12] Gao B, Stieger B, Noe B, Fritschy JM, Meier PJ: Localization of the
organic anion transporting polypeptide 2 (Oatp2) in capillary
endothelium and choroid plexus epithelium of rat brain. Journal of
Histochemistry & Cytochemistry 1999; 47: 1255-64.
[13] Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB: OATP and
P-glycoprotein transporters mediate the cellular uptake and excretion of
fexofenadine. Drug Metabolism & Disposition 1999; 27: 866-71.
[14] Schinkel AH, Wagenaar E, Mol CA, van Deemter L: P-glycoprotein in
the blood-brain barrier of mice influences the brain penetration and
pharmacological activity of many drugs. Journal of Clinical
Investigation 1996; 97: 2517-24.
[15] Dagenais C, Graff CL, Pollack GM: Variable modulation of opioid brain
uptake by P-glycoprotein in mice. Biochemical Pharmacology 2004; 67:
269-76.
[16] Ayrton A, Morgan P: Role of transport proteins in drug absorption,
distribution and excretion. Xenobiotica 2001; 31: 469-97.
[17] Verschraagen M, Koks CH, Schellens JH, Beijnen JH: P-glycoprotein
system as a determinant of drug interactions: the case of digoxinverapamil.
Pharmacological Research 1999; 40: 301-6.
[18] Iman A Elkiweri, Yan Ling Zhang, Uwe Christians, Ka-Yun Ng,
Martha C Tissot van Patot, Thomas K Henthorn : Competitive substrates
for P-glycoprotein and organic anion protein transporters differentially
reduce blood organ transport of fentanyl and loperamide:
pharmacokinetics and pharmacodynamics in Sprague-Dawley rats.
Anesth Analg.2009; 108: 149-159.
@article{"International Journal of Biological, Life and Agricultural Sciences:63525", author = "Iman A. Elkiweri and Ph.D and Martha C. Tissot van Patot and Ph.D. and Yan Ling Zhang and Ph.D. and Uwe Christians and Ph.D. and Thomas K. Henthorn and M.D. and ", title = "The Effect of Loperamide and Fentanyl on the Distribution Kinetics of Verapamil in the Lung and Brain in Sprague Dawley Rats", abstract = "Verapamil has been shown to inhibit fentanyl uptake in vitro and is a potent P-glycoprotein inhibitor. Tissue partitioning of loperamide, a commercially available opioid, is closely controlled by the P-gp efflux transporter. The following studies were designed to evaluate the effect of opioids on verapamil partitioning in the lung and brain, in vivo. Opioid (fentanyl or loperamide) was administered by intravenous infusion to Sprague Dawley rats alone or in combination with verapamil and plasma, with lung and brain tissues were collected at 1, 5, 6, 8, 10 and 60 minutes. Drug dispositions were modeled by recirculatory pharmacokinetic models. Fentanyl slightly increased the verapamil lung (PL) partition coefficient yet decreased the brain (PB) partition coefficient. Furthermore, loperamide significantly increased PLand PB. Fentanyl reduced the verapamil volume of distribution (V1) and verapamil elimination clearance (ClE). Fentanyl decreased verapamil brain partitioning, yet increased verapamil lung partitioning. Also, loperamide increased lung and brain partitioning in vivo. These results suggest that verapamil and fentanyl may be substrates of an unidentified inward transporter in brain tissue and confirm that verapamil and loperamide are substrates of the efflux transporter P-gp.
", keywords = "Efflux transporter, elimination clearance, partition coefficient, verapamil", volume = "3", number = "7", pages = "372-6", }
