*3.7. Transporter-CYP450 Interplay in Intestine*

Some drugs are often substrates of various transporters and CYP3As. Alterations in oral plasma exposure of drug should be attributed to common effects of the altered transporters and CYP3As. For example, atorvastatin is a substrate of intestinal P-gp, BCRP and OATPs, indicating that the Peff of atorvastatin should be the integrated effects of passive diffusion, OATP1A5-mediated absorption, P-gp mediated efflux and BCRP-mediated efflux. Diabetes also downregulated the expression of intestinal OATP1A5 [11]. Thus, the Peff of atorvastatin under diabetic status should be the net effects of these altered transporters. Downregulation of intestinal CYP3A expression by diabetes was also involved in the first-pass effect of atorvastatin. PBPK simulation demonstrated that contributions of intestinal transporters and CYP3A was intestinal BCRP > intestinal CYP3A > intestinal P-gp > intestinal OATP1A5 [11]. Cyclosporin A is also a substrate of BCRP, OATPs, CYP3A and P-gp, indicating that increased oral plasma exposure of cyclosporin A in diabetic rats [111] was also partly attributed to the common effects of the intestinal transporters and CYP3A. Verapamil is a substrate of P-gp and CYP3As. PBPK simulation also showed that the contribution of intestinal P-gp was much larger than that of intestinal CYP3A [93], indicating that increased oral plasma exposure of verapamil [27] was mainly attributed to downregulation of intestinal P-gp. Grepafloxacin [112] is also a substrate. Decreased expression of BCRP may partly explain why the decreased secretory transport of grepafloxacin was not in line with the decrease in expression of P-gp protein in diabetic rats [84]. Similarly, intestinal OATP1A5 also mediates intestinal absorption of glibenclamide [113], inferring that the increased Peff

of glibenclamide by impairment of intestinal BCRP [48] may be partly weakened by the decreased expression of OATP1A5 protein.

#### **4. Kidney**

Drugs are eliminated in the kidney via urinary excretion. The process consists of glomerular filtration, secretion and reabsorption at the renal tubule. The secretion and reabsorption are mainly mediated by transporters. The identified renal transporters include OAT1/3, OCT1/2, PepT1/2, MATE1, MATE2/K, P-gp, BCRP, MCTs and urate transporter 1 (URAT1) (Figure 3A). Transporter interplay occurs at the kidney. For example, metformin, a substrate of OCTs and MATEs, is taken in renal epithelial cells via OCT1/2 at the basolateral membrane, then secreted into urine via MATEs at the brush-border membrane of renal tubular cells, mediating the renal excretion of metformin. The transporter interplay also participates in renal excretion of uric acid. URAT1, OAT1, OAT3, OAT4, OAT10, BCRP, sodium-dependent phosphate transport protein 1/4 (NPT1/4) and glucose transporter 9 (GLUT9) work together to regulate the excretion of uric acid via the kidney [114] (Figure 3B).

**Figure 3.** (**A**) Possible location of main transporters in human kidney and (**B**) roles of transporter interplay in renal excretion of uric acid. Symbol: OATPs, organic anion transporting polypeptides; OATs, organic anion transporters; OCTs, organic cation transporters; PepTs, peptide transporters; P-gp, P-glycoprotein; MRPs, multidrug resistance-associated proteins; BCRP, breast cancer resistance protein; MATEs, multidrug and toxin extrusion, NPTs, sodium-dependent phosphate transport proteins, GLUT9, glucose transporter 9, URAT1, urate transporter 1.
