**1. Introduction**

The pharmacokinetics of a drug is determined by absorption, distribution, excretion and metabolism. Drug absorption, distribution and excretion are mainly controlled by drug transporters, while drug metabolism is mediated by metabolic enzymes. These drug transporters are classified into the ATP binding cassette (ABC) family and the solute carrier (SLC) family. The main SLC transporters involved in drug transport are multidrug/toxin extrusions (MATEs), organic anion transporting polypeptides (OATPs), monocarboxylate transporters (MCTs), organic anion transporters (OATs), peptide transporters (PepTs), and organic cation transporters (OCTs). Most SLC transporters belong to influx transporters, except for MATEs. The identified ABC transporters related to drug efflux include P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). These transporters are widely expressed in the intestine, liver and kidney. They affect drug therapeutic effects/toxicity via regulating drug uptake or secretion. Enzymes involved in drug metabolism mainly include cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs). These enzymes are also widely distributed in the liver, intestine and kidney. Drug disposition in tissues is highly dependent on the coordinate work of these influx transporters, enzymes and

efflux transporters, termed as the "interplay of transporters and enzymes" [1–3]. Moreover, multiple SLC transporters, ABC transporters and enzymes often participate in the disposition of drugs. A typical example is atorvastatin. Atorvastatin is a substrate of P-gp, MRP2, BCRP, OATP1B1, OATP1B2, OATP2A1, CYP3A4/5 [4] and UGTs [5,6]. Sodium taurocholate co-transporting polypeptide (NTCP) also mediates hepatic uptake of atorvastatin [7]. In the liver, atorvastatin enters hepatocytes from portal blood mainly via influx transporters at the basolateral surface of hepatocytes. In hepatocytes, atorvastatin is metabolized via CYP3As or UGTs. Atorvastatin and its metabolites are excreted into bile via efflux transporters (MRP2, BCRP and P-gp) or returned to the blood via MRP3 [8]. The transporter–enzyme interplay also occurs in the intestine and kidney. Accumulating studies [9–12] have demonstrated that diabetes remarkably alters the expression and functions of drug transporters and CYP450s, disordering transporter-CYP450 interplay and in turning affecting the disposition of corresponding drugs, their therapeutic efficacy or drug toxicity. Here, we aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to alterations in the expression of influx transporters, efflux transporters and CYP450s under diabetic status; (2) the net contributions of the altered expressions and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically based pharmacokinetic model (PBPK) in the imbalance of transporter–enzyme interplay under diabetic conditions.

#### **2. Liver**

Drugs are eliminated in the liver mainly via metabolism and biliary excretion. The liver highly expresses various drug transporters (such as P-gp, BCRP, MRPs, OATPs, OCTs, OATs and MATEs) (Figure 1A) and drug metabolic enzymes (such as CYP450s and UGTs). They work in series to control the disposition of drugs in the liver (Figure 1B).

**Figure 1.** (**A**) Possible location of main transporters in liver. (**B**) Transporter–enzyme interplay in the elimination of drugs in the liver. Symbol: BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CA, concentrations of drug in arterial blood; CLint,all, overall hepatic intrinsic clearance; CLint,up, intrinsic uptake clearance; CLint,back, intrinsic clearance of backflux to blood; CLint,met, intrinsic metabolism clearances; CLint,bile, biliary clearance of unbound drug; CV, concentrations of drug in venous blood; MATEs, multidrug/toxin extrusion; MRPs, multidrug resistance-associated proteins; NTCP, sodium taurocholate co-transporting polypeptide; OATs, organic anion transporters; OATPs, organic anion transporting polypeptides; OCTs, organic cation transporters; QH, hepatic blood flow; P-gp, P-glycoprotein.

#### *2.1. OATPs*

OATPs, expressed at the basolateral membrane of hepatocytes, mediates hepatocyte uptake of many anions from the blood, which becomes a rate-limited process of hepatic clearances for some drugs [3]. It was found that in diabetic rats (type 2 diabetes) induced by a streptozocin (STZ) and high-fat diet (HFD) combination (termed as STZ/HFD), hepatic OATP1B2 (rodent orthologue of human OATP1B1 and OATP1B3) is remarkably induced, leading to increased hepatic uptake of repaglinide [9,10], atorvastatin [9,11] and simvastatin [12] as well as hepatic clearances [9,11]. In line with this, the diabetic rats showed lower plasma concentrations of atorvastatin [9,11], simvastatin [12] and pravastatin [13] compared with control rats. Clinical trials also showed that tuberculosis patients with diabetes showed significantly lower concentrations of rifampicin than non-diabetic patients [14,15], which may be attributed to the induction of hepatic OATPs by diabetes and rifampicin.
