Importance Of Drug Interactions In Early Drug Development Biology Essay

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Should drug interactions occurring at transporters be taken into account early in drug development, in addition to metabolism-mediated interactions?


The main objective of a drug administration in our body is to prevent, cure from the disease or to control various disease condition; to achieve this goal drug doses should be adequate and should be well adjusted in our body (Mycek et al., 2000). Again, the efficacy of a drug depends on complex interrelation of different pharmacokinetic process; such as, intestinal absorption, the distribution of drug into blood and tissue, phase-І and phase-ІІ metabolism renal or fecal excretion and all these provide desired concentration of a drug at the site of molecular target {(Chan et al., 2004; Jeong et al., 2005; Wu & Benet, 2005) cited by Oswald et al., 2007}. However, drug interaction can play an important role to change systemic exposure and in turn may affect the co administered drugs. For several decades, metabolism mediated drug interaction was the main focus of research as well as for drug development (Funk, 2008) and also was an integral part of a regulatory review before marketing a new drug (Bode, 2009). Now-a-days in addition to this, transporter-based interactions have been increasingly documented; and it has been revealed that drug transporters can play an essential role in modulating the pharmacokinetic of a drug either alone or in combination with drug-metabolizing enzymes (Funk, 2008; Zhang et al., 2008; Bode, 2009). Herein some major transporters involved in drug absorption, distribution, metabolism, and elimination have been briefly reviewed, along with the substrates & drug interactions demonstrated nowadays.

Transporters & their role in drug interaction:

Transporters are the membrane proteins that mainly involve in controlling the influx of essential nutrients, ions & efflux of cellular waste, toxins, and xenobiotics from the body (Brunton et al., 2008). Two major super families - ATP binding cassettes (ABC) and solute carrier transporter covers the area of transporter; ABC are primary active transporter and they are classified as ABCA-ABCG. SLCs are mainly facilitated or ion coupled secondary active transporters (Brunton et al., 2008; Oswald, et al.,2007;Funk, 2008) stated that, different transporter e.g. P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) or organic anion transporting polypeptides (OATPs) are responsible for overall deposition and efficacy of certain drugs. Furthermore, transporters which are related to certain drugs' uptake or efflux are important for a drug development; for example-breast cancer resistance protein (BCRP) are widely distributed in gut, liver and kidney and causes drug efflux,thus contribute to eliminate potentially toxic compounds from our body; statins, antibiotics, human immunodeficiency virus (HIV) protease inhibitors, immunosuppressant, anticancer and cardiac drugs are the substrates of this efflux carriers.{(Chan et al., 2004; Endres et al., 2006) cited by Oswald et al., 2007}.Some of the important transporters and their impact on drug interaction as well as on drug development are discussed in the paragraphs ahead.

Organic anion transporting polypeptides (OATPs):

They are widely distributed in organs, which are involved in drug absorption, distribution and elimination,e.g. liver, kidney, intestine, brain and placenta{(Tamai, et al., 2000; Ayrton & Morgan., 2001; Hagenbuch & Meier., 2003) cited by Aryton, et al., 2008}. The OATP family includes OATP1B1 (OATP-C) and OATP1B3 (OATP-8) are specifically distributed on the sinusoidal membrane of hepatocytes {(Konig et al., 2000 a, b; Ito et al., 2005) cited by Aryton et al., 2008}.OATPs are responsible for several drugs' uptake and hence, can increase the availability of drugs for metabolism by hepatic enzyme and also for biliary excretion (Aryton et al., 2008).Statin class of drugs whose main site of action is liver, OATPs can help these drugs to enter the hepatocyte and can prevent the side effect such as myopathy, rhabdomyolysis caused by exposure this drugs to muscles(Aryton et al., 2008, Helms et al., 2006).Furthermore,drug-drug interaction can inhibit OATP1B1 transport of statin; the interactions between rosuvastatin or pravastatin with gemfibrozil causes twofold increase in plasma exposure of each statin {(Backman et al., 2000, 2002; Kyrklund et al., 2001; Mikkaichi et al., 2004; Schneck et al., 2004) cited by Aryton et al., 2008; Helms et al., 2006)}. Similarly, interaction of rosuvastatin and cyclosporine is also the evidence of OATP mediated hepatic uptake inhibition (Helms et al,. 2006). Parvastatin, which is a cholesterol synthesis enzyme inhibitor and OATP1B1 is responsible for its uptake in liver {(Kivisto et al,. 2007) cited by Oswald et al., 2007}, if co-administrated with rifampicin {although known as enzyme inducer (Helms et al., 2006) and cyclosporine; its plasma concentration and overall deposition increased; due to OATP mediated uptake inhibition(Oswald et al., 2007; Qiang et al., 2009), studied that, the concurrent use of fexofenadine prior to fluvastatin in rats, causes decrease in fluvastatin bioavailability and plasma clearance by 44% and opposite is also true for fexofenadine, when pretreatment was done with fluvastatin;it might be due to both drugs interact with OATPs that present in intestine and liver, compete for the OATP mediated transport pathways. Moreover, it has been demonstrated that OATP-C is also important from physiological point as it can transport bilirubin & its mono and diglucoronide (Cui et al., 2001b cited by Mizuno et al., 2003). So, OATP transporters are important as they play a significant role in certain drugs elimination and efficacy: likewise, the interaction between other drugs with their substrate can lead to adverse drug effect in human body.

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Figure 1 - Major solute carriers and ABC exporters involved in hepatic drug transport Figure taken from Funk, (2008).

The bile salt export pump BSEP (ABCB11):

The bile salt export pump is expressed at the canalicular membrane, responsible for the export of conjugated and unconjugated bile salts into the canalicular space & inhibition of BSEP can cause an impaired bile flow & cholestasis (Funk 2008). It has been demonstrated that drugs like cyclosporine A, rifampicin, rifamycin, bosentan, flutamide, troglitazone and glyburide can induce cholestasis and also reported that they are in vitro inhibitors of BSEP {(Fattinger et al., 2001; Funk et al., 2001; Byrne et al.,  2002; Iwanaga 2007; Mita et al., 2006; Mano et al.,) cited by Aryton et al., 2008)}.

P-Glycoprotein(MDR1, ABCB1):

They are efflux pump and belongs to the ATP-binding cassette transporter super-famaily; they are mainly distributed in the luminal surface of intestinal epithelia, renal proximal tubule, the placenta, blood brain barrier and the bile canalicular membrane of hepatocyte{(Aryton & Morgan, 2001) cited by Aryton et el., 2008}. When a drug is taken orally and during its passage through enterocyte, P-gp picks up the molecule and back to luminal side of cell; thus P-gp limits the bioavailability of that drug, while the P-gp in liver and kidney acts to increase the excretion of drugs by transporting the molecules into bile and urine accordingly(Horn, 2004).Furthermore, if the activity of P-gp is inhibited, more drugs will be absorbed which will increase plasma concentration, on the other hand the drugs those normally eliminated by P-gp will accumulate in the body and opposite is also true in case of p-gp inducer (Horn, 2004). So, P-gp plays an important role in absorption, distribution and elimination of their substrate and also for the substrate specifity, their inhibitor and inducers are important for drug interaction (Aryton et al., 2008; Aszalos, 2007), studied that, co-administration of the antifungal agent itraconazole and digoxin causes elevation of the serum concentration of digoxin and decreases renal clearance of digoxin;due to itraconazole modulates the function of P-gp. Furthermore, a study conducted by Hedman et al., 1991 (cited by Aryton, et al., 2008) on healthy volunteers, who simultaneously infused by digoxin and quinidine showed that quinidine reduces both biliary and renal secretion of digoxin. The inhibition might be caused by a very high affinity of quinidine for P-gp or ATP hydrolysis at ATP binding site or it inhibit protein kinase-C that involves with ATP coupling to P-gp (Wang et al., 2003 cited by Zhou, 2008; Chang et al., 1996), also demonstrated that absorption of cyclosporine which is an immune suppressor drug can be increased if the water-soluble vitamin E derivative inhibits the p-gp transporter and flavonoid (Brand et al., 2006) can inhibit ABC transporter and may increase the bioavailability of other drugs. The presence of p-gap in blood brain barrier can protect our brain from adverse drug effect and also can prevent drug deposition, which is evidenced by the substrate of p-gp like loperamide, cetrizine and fexofenadin: all have lack of central side effects and the lack of central sedating effects {(Polli et al., 2003; Cvetkovic et al., 1999) cited by Aryton, et al., 2008}. Again, HIV can penetrate the brain and cause neurological complication, it is so highly expected that HIV protease can cross the BBB and exert antiviral effect on brain(Lin, 2007).But, for the presence of P-gp at BBB,many HIV protease cannot delivered to the brain effectively such as,anti-HIV-1 drug abacavir cannot distribute to the CNS due to p-gp mediated efflux at the blood brain barrier(Shaik et al., 2007) and this can be overcome by co administration of ketoconazole ,which is both the inhibitor of p-gp and CYPs (Lin, 2007). Besides this, Induction of p-gp transporter by drugs may cause treatment failure; for instance, with the use of complementary and alternative medicine(CAM) in combination with conventional chemotherapeutics, causes  Induction of drug-metabolizing enzymes and also ATP-binding cassette  drug transporters, which leads to lower plasma levels of the anticancer drugs and eventually therapeutic failure occurs (Meijerman et al., 2006). Moreover, P-gp is also over expressed in tumor cells, which deliberately efflux anti cancer drugs and thus responsible for the drug resistance in cancer chemotherapy (Lin, 2007). It has also been reported (Lin, 2007) that, a significant increase in systemic exposure was occurred with the concurrent use of PSC-833 or GF-120918 due to inhibition of P-gp function. There are certain drugs which may induce both CYP and P-gp and thus can alter the pharmacokinetic of the drug which is the substrate for both CYP and p-gp (Lin, 2007), reported this type of drug interaction in case of rifampicin which is an inducer of both CYP and P-gp and cyclosporine which is a substrate of CYP and P-gp; rifampicin, decrease the bioavailability and increase the eliminitation clearance of cyclosporine. As, the pharmacokinetics, efficacy and safety of a drug can be greatly influenced by these transporters; so, p-gp mediated drug interaction is important and needs to be considered before developing a drug.


Figure 2 - Distribution of P-gp in several tissues in human and P-gp functions as an efflux pump, preventing the entry of xenobiotics into these tissues. Figure taken from Endres et al. (2006).

Breast cancer resistance protein (BCRP):

They are also the member of ATP binding cassette efflux family (Zhao et al., 2009) and are mainly distributed in intestine, blood brain barrier, blood testis barrier and liver canalicular membrane and are involved in biliary secretion of fluroquinolone antibiotics, e.g. grepafloxacin, ulifloxacin, ciprofloxacin and ofloxacin, used in the treatment of biliary infections (Ando et al., 2007 cited by Aryton et al., 2008); but they play a minor role in efflux of different substrate at BBB (Zhao et al., 2009). It has been demonstrated (Breedveld et al., 2004 cited by Aryton, et el., 2008) that, pentoprazole, which is a BCRP inhibitor can suppress the efflux of methotrexate and as a result methotrexate absorption increased from this region. Breedveld et al., 2004 (cited by Aryton et el., 2008) studied co-administration of methotrexate with pantoprazole and omeprazole in cancer patient can cause methotrexate induced toxicity, as pantoprazole and omeprazole are Bcrp inhibitors. So, the role of Bcrp in absorption of drug can be assumed from this study. Kis et al. ( 2009) demonstrated that, leflunomide and its metabolite inhibited BCRP-mediated methotrexate transport and increased methotrexate concentration in plasma and they also studied that BCRP can play an important role in the resistance to leflunomide and its metabolite A771726 by interacting with these drugs. So, it can be assumed that, transporters are also important in developing drug resistance and can play role in diminishing the drug effect.

OAT (organic anion transporter):

Organic anion transporters OAT1, OAT2, OAT3, OAT4, and URAT1 are mainly located in kidney (Koepsell & Endou, 2004 cited by Aryton et al., 2008). They are also present in liver, placenta and brain; they play an important role in drug excretion by kidney and also play role in deposition of some drugs, such as antibiotics, anti-hypertensives, diuretics and antiviral drugs (Aryton et al., 2008). OAT substrates such as methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs) are secreted by the renal tubular cells and renal tubular secretion is their primary method of elimination (Horn & Hasten, 2009). Masuda et al. (1997) showed in their study on cloned rat kidney - specific anion transporter OAT-K1 that, non-steroidal anti-inflammatory drugs such as indomethacin, ketoprofen can inhibit this transporter and are responsible for methotrexate accumulation (inhibit the OATK-1 mediated methotrexate transport) in kidney after co-administration and thus OAT-K1 is one of the interaction site for methotrexate and NSAIDs in renal excretion. Furthermore, HMG-CoA reductase inhibitors such as pravastatin and cerivastatin are partially dependent on OATs for their elimination and when an OAT inhibitor like cyclosporine are co-administered with these drugs, it increases the plasma concentration of these statins (Horn & Hasten, 2009) consequently adverse effect of these drugs will be more pronounced. So, an OAT-mediated interaction is important for the drugs which are its substrate, as their renal clearance largely depends on this transporter. Besides this, OAT expression in other tissues such as the liver, intestine, and the brain can contribute to important drug interactions in these sites (Endres et al., 2006).

OCT (organic cation transporter):

These transporters are responsible for the uptake of organic cations in different types tissues and play an important role in the detoxification of many exogenous substances (Ciarimboli, 2008; Aryton et al., 2008); they mainly involve in the transporting heterocyclic weak bases, such as endogenous compounds (e.g. dopamine, epinephrine and choline) as well as different types of drugs (Endres et al., 2006). Two types OCT1 and 2,are primarily present on the basolateral membrane of epithelial cells in the renal proximal tubule (Wright & Dantzler, 2004 cited by Endres et al., 2006 ) and can also be expressed in kidney, liver and placenta (Wright & Dantzler, 2004 cited by Endres, et al., 2006). A number of OCT mediated drug interaction have been showed, for example any substrates such as tetraethyl ammonium, N-methyl-4-phenylpyridine (MPP+), choline, N-methylnicotinamide and metformin and its inhibitors like cimetidine, quinidine and verapamil (Urakami et al., 1998 cited by Aryton et al., 2008) when co-administered, the concentration of substrates of OCT increases as their overall elimination is inhibited. It was demonstrated (Yuan et al., 2009) that co-administration of the fibrate gemcabene (CI-1027) with the angiotensin-converting enzyme inhibitor quinapril causes elevation of plasma concentration of quinapril in humans and rats, due to inhibition of OATs by gemcabene; as a result a synergistic blood pressure reduction was observed. Hence, OCT interactions have the greatest influence on the active tubular secretion in the kidney and inhibition of these transporters can affect its substrate excretion; the OCT inhibition may also affect drug distribution into other organs (e.g. liver and placenta) due to its broad tissue expression(Endres et al., 2006).

Peptide transporter (PEPT) :

The oligopeptide transporters (PEPT-1, SLC15A1),are distributed in the intestinal brush border membrane of the human intestine and plays an important role in peptide absorption (Adibi 1997 cited by Endres et al., 2006). Substrate of this transporter includes oral β-lactam antibiotics (Terada et al., 1998 cited by Endres et al.2006), the anticancer agent bestatin (Gonzalez et al., 1998 cited by Endres et al.,2006) and the angiotensin-converting enzyme inhibitors (enalapril and temocapril) (Boll et al., 1994 cited by Endres et al.,2006) and cephalosporin which is reported to inhibit PEPT can reduce all these substrate to be absorbed at intestinal level (Endres et al., 2006). Furthermore, The inhibitors of PEPT (PEPT-1 & PEPT-2) includes the novel oral hypoglycemic agent nateglinide (AY4166) (McAleer et al., 1999 cited by Endres et al., 2006) and epidermal growth factor (Bravo et al., 2003) which may also contribute to PEPT mediated drug interaction. However, PEPT-1 interactions most occur at the level of intestinal absorption, whereas PEPT-2 interactions will most likely occur at the level of renal secretion and PEPT-mediated drug - drug interactions are important in therapy and toxicology (Endres et al., 2006).

Multiple drug therapy is recommended in many disease states such as AIDS, cancer, diabetes, and stroke; drug interactions can play an important role in changes in pharmacological or toxicological response following co administration of many therapeutic agents and transporters that are located in intestinal, renal and hepatic epithelia can contribute to this interaction either alone or in concert with drug metabolizing enzyme through in the process of selective absorption and elimination of drugs (Pal et al., 2006). Therefore, a wide variety of drugs interaction can be mediated through the transporter, which can alter the efficacy of the affected drug as well as sometimes lead to a toxic effect.


The information on the characteristics of drug transporters can help the pharmaceuticals to improve drug delivery and also for drug designing by targeting a specific transporter protein (Mizuno et al., 2003). Moreover, drug interactions involving transporters often causes adverse effect on therapeutic safety and efficacy of many drugs (Mizuno et al., 2003). So, the contribution of drug transporter to drug ADME and their interaction with different drugs needs to be considered throughout the drug discovery and development in addition to metabolism based interaction, where enzyme induction and inhibition is the main focus. Then many adverse effects due to drug deposition in human body can be avoided efficiently as well as efficacy of drugs used in different disease states will be significantly increased, even at a minimal dose.