In vitro model Effects on Rho 123 Rho 123 Detection Ref.
MV522 Verapamil decreased Rho 123 accumulation factor but not PSC833 Fluorescence Spectro-photometry [78]
MV522/Q6 PSC833 increased Rho 123 accumulation factor but not verapamil
KB-3-1 Verapamil and PSC833 decreased Rho 123 accumulation factor
KB-8-5 Verapamil and PSC833 increased Rho 123 accumulation factor
PBMC Several P-gp inhibitors increased intracellular Rho 123 fluorescence Flow Cytometry [88]
LLC-PK1 R(B-A/A-B): 10.0 HPLC-FL [89]
L-MDR1 R(B-A/A-B): 3.3
After addition of PSC833, cyclosporin A, verapamil, quinine, cimetidine and TEA: Papp (B-A) decreased by 56%, 21%, 55%, 33%, 34% and 40%.
Caco-2 R(B-A/A-B): 81.0
After addition of PSC833, cyclosporin A, verapamil, quinine:
Papp (B-A) of Rho 123 decreased by 88%, 82%, 70% and 82%.
After addition of cimetidine and TEA: no changes.
  R(B-A/A-B) > 10.0
After addition of GW918: R(B-A/A-B) ≈ 1		 Fluorescence Spectro-photometry [90]
  Papp (B-A) substantially higher than Papp (A-B)
After verapamil or quinidine addition (100 µM):R(B-A/A-B) ≈ 1		 Fluorescence Spectro-photometry [91]
Everted rat intestine sac Papp (B-A) significantly enhanced after verapamil addition (300 µM).
Animal Studies Brief Procedure Effects on pharmacokinetics of Rho 123 Rho 123 Detection Ref.
Mdr1a (-/-) Mice Rho 123 (9 nmol/min, IV) In comparison to wild-type mice, mdr1a (-/-) mice showed:
similar plasma concentrations;
brain concentration 4-fold higher;
higher brain/plasma ratio.		 HPLC-FL [87]
Sprague-Dawley Rat Cyclosporin A (10 mg/Kg, IV)
Rho 123 (174 µg/h, IV). 		Cyclosporin A:
reduced renal secretory clearance by 62.9%;
reduced CLB by 30.9%.		 Fluorimetry [84]
Wistar Rat Rho 123 (10 mg/Kg, IV)  Cyclosporin A (1 mg/Kg/h, IV) Cyclosporin A:
No influence on plasma PK;
AUCCEF increased from 0.94 to 3.41 µg.mL/min;
AUCbrain/AUCplasma ratio enhanced from 0.59% to 2.17%.		 HPLC-FL [85]
  Cyclosporin A
(5, 10, 15 and 20 mg/Kg, IV)
Rho 123 (0.2 mg/Kg, IV) 		Cyclosporin A pre-treatment decreased CLB by 64-85%. Fluorometry [92]
IP dexamethasone for 4 days
Rho 123 (25 μg/Kg at bolus followed constant infusion at 4 mL/h).		 In comparison to untreated rats, dexamethasone pre-treatment:
increased urine flow rate 2.5-fold;
increased CLB by 1.5-fold;
increased CLR by 4.1-fold		 - [93]
Cyclosporin A (10 mg/Kg/mL, IV)
30 min after:
Rho 123 (0.2 mg/Kg/mL)		 Cysclosporin A pre-treatment:
decreased t1/2 by 19.2%;
increased Cmax by 64.7%;
increased AUC0-t by 26.5%;
decreased CLT by 24.6%.		 Fluorimetry [83]
Table 3: In vitro and in vivo studies in which Rhodamine 123 (Rho 123) demonstrated to be a substrate of P-gp. AUC, area under the curve; CEF, cortex extracellular fluid CLB, biliary clearance; CLR, renal clearance; FL, fluorescence; HPLC, high performance liquid chromatography; IV, intravenous; IP, intraperitoneal; KB-3-1,; KB-8-5, human epidermoid carcinoma cell multidrug resistant; LLC-PK1, porcine kidney tubular cell line; L-MDR1, porcine kidney tubular cell line transfected with human MDR1 gene; MV522, human metastatic lung carcinoma cells; MV522/Q6, human metastatic lung carcinoma cells transfected with high levels of human MDR1 gene; Papp, apparent permeability; PBMC, peripheral blood mononuclear cells; R(B-A/A-B), efflux ratio given by the ratio between apparent permeability in efflux (B-A) and absorption (A-B) directions; t1/2 elimination half-life; TEA, tetraethylammonium; tmax, time to reach maximum concentration (Cmax).
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