The drug transporter-metabolism alliance: uncovering and defining the interplay

Abstract

Two decades ago the importance of transporter-enzyme interplay and its effects on drug bioavailability and hepatic disposition were first recognized. Here we review the history of uncovering and defining this interplay with a primary emphasis on studies from our laboratory. We review the early 1990s oral bioavailability studies that found that the highly lipophilic, poorly water-soluble cyclosporine formulation on the market at that time did not have an absorption problem, but rather a gut metabolism problem. This led to studies of the interactive nature of CYP3A and P-glycoprotein in the intestine, and investigations of this interplay using cellular systems and isolated perfused rat organ studies. Studies investigating uptake transporter-enzyme interactions using cellular, perfused rat liver and intact rats are reviewed, followed by the human transporter-enzyme interaction studies. Work characterizing the rate limiting processes in the drug transporter-metabolism alliance is then addressed, ending with a review of areas of the interplay that require further studies and analysis.

Figure 1

Cartoon depicting CYP3A4 and P-glycoprotein interplay in the enterocytes.

Figure 2

Extraction ratios of K77 and felodipine after an apical or basolateral dose. The effect of inhibiting P-glycoprotein on the extraction ratio is unmasked by incubating the substrates with GG918, whereas the dual effect of inhibiting CYP3A4 and P-glycoprotein on the extraction ratio is elucidated by inhibiting with cyclosporine (CsA). Data are presented as the mean ± S.D. (n=3).

Figure 3

Perfusate concentration-time profile for tacrolimus (A) and felodipine (B) without (control) and in the presencne of three different P-glycoprotein/CYP3A inhibitors over 30 min.

Figure 4

The special relationship between the enzyme and efflux transporter in the intestine and the liver.

Figure 5

Mean plasma concentrations (± S.D.) of (A) atorvastatin acid; (B) atorvastatin lactone; (C) 2-hydroxy-atorvastatin acid; (D) 2-hydroxy-atorvastatin lactone; (E) 4-hydroxy-atorvastatin acid, and (F) 4-hydroxy-atorvastatin lactone in 11 healthy volunteers after a single oral dose of 40 mg atorvastatin with and without 600 mg rifampin given as an intravenous 30-min infusion. The insets depicts the same data on a semilogarithmic scale. Solid circles indicate the atorvastatin-alone control group; open circles indicate the rifampin-treatment group.

Figure 6

Transporter effects predicted by BDDCS in the gut and the liver.

Figure 7

In vivo and in vitro techniques to determine the scaling factors for the hepatobiliary transport of drugs. Q: hepatic blood flow rate, Ca: drug concentration in the arterial blood, Cv: drug concentration in the hepatic venous blood, PS_inf: intrinsic uptake clearance, PS_eff: intrinsic clearance for sinusoidal efflux, PSint, bile: intrinsic clearance for the biliary excretion, CL_{int, met}: intrinsic clearance for metabolism.