Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.

Impact of Drug Transporter Studies on Drug Discovery and Development

Since its approval in 1983 for immunosuppressive therapy in patients undergoing organ and bone marrow transplants, cyclosporin has had a major impact on organ transplantation. It has significantly improved 1-year and 2-year graft survival rates, and decreased morbidity in kidney, liver, heart, heart-lung and pancreas transplantation. Several studies have supported the efficacy of cyclosporin in preventing graft-versus-host disease in bone marrow transplantation. Cyclosporin is also possibly effective in treating diseases of autoimmune origin and as an antineoplastic agent. The introduction of therapeutic drug monitoring of cyclosporin was extremely useful because of the wide inter- and intraindividual variability in the pharmacokinetics of cyclosporin after oral or intravenous administration. Optimal long term use of cyclosporin requires careful monitoring of the blood (or plasma) concentrations. Sustained and clinically significant drug-drug interactions can occur during long term therapy with cyclosporin. The coadministration of multiple drugs with cyclosporin could result in graft rejection, renal dysfunction or other undesirable effects. Any interaction that leads to modified cyclosporin concentrations is of potential clinical importance. Cyclosporin itself may have significant effects on the pharmacokinetics and/or pharmacodynamics of coadministered drugs, such as digoxin, HMG-CoA reductase inhibitors and antineoplastic drugs affected by multidrug resistance. Many drugs have been shown to affect the pharmacokinetics and/or pharmacodynamics of cyclosporin. Interactions between cyclosporin and danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, metoclopramide, nicardipine, verapamil, carbamazepine, phenobarbital (phenobarbitone), phenytoin, rifampicin (rifampin) and cotrimoxazole (trimethoprim/sulfamethoxazole) are well documented in a large number of patients. Other interactions (such as those with aciclovir, estradiol and imipenem) are documented only in isolated case studies.

Clinically Significant Drug Interactions with Cyclosporin An Update

Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine.

Macrolide antibacterials. Drug interactions of clinical significance.

Cytochrome P450 (P450) is the collective term for a group of related enzymes or isozymes which are responsible for the oxidation of numerous drugs and other foreign compounds, as well as many endogenous substrates including prostaglandins, fatty acids and steroids. Each P450 is encoded by a separate gene, and a classification system for the P450 gene superfamily has recently been proposed. The P450 genes are assigned to families and subfamilies according to the degree of similarity of the amino acid sequences of the protein part of the encoded P450 isozymes. It is estimated that there are between 20 and 200 different P450 genes in humans. The human P450IID6 is a particular isozyme which has been extensively studied over the past 10 years. The P450IID6 is the target of the sparteine/debrisoquine drug oxidation polymorphism. Between 5 and 10% of Caucasians are poor metabolisers, and it has recently been shown that the P450IID6 enzyme is absent in the livers of these individuals. The defect has also been characterised at the DNA and messenger RNA (mRNA) level, and to date 3 different forms of incorrectly spliced P450IID6 pre-mRNAs have been identified in the livers of poor metabolisers. The P450IID6 has a broad substrate specificity and is known to oxidise 15 to 20 commonly used drugs. The metabolism of these drugs is therefore subjected to the sparteine/debrisoquine oxidation polymorphism. The clinical significance of this polymorphism for a particular drug is defined according to the usefulness of phenotyping patients before treatment. It is concluded that this strategy would be of potential value for tricyclic antidepressants, some neuroleptics (e.g. perphenazine and thioridazine) and some anti-arrhythmics (e.g. propafenone and flecainide). The P450IID6 displays markedly stereoselective metabolism and appears uninducible by common inducers like rifampicin and phenazone (antipyrine). With some substrates, such as imipramine, desipramine and propafenone, P450IID6 becomes saturated at therapeutic doses. Finally, its function is potently inhibited by many commonly used drugs, for example, quinidine. The most clinically relevant interaction in relation to P450IID6 function appears to be the potent inhibition by some neuroleptics of the metabolism of tricyclic antidepressants. No drug-metabolising P450 has been so well characterised at the gene, protein and functional levels as the P450IID6. This development is based on an extensive use of specific model drugs, the oxidation of which in vitro and in vivo is dependent on the function of P450IID6; it can be expected that other human drug-metabolising P450s will be similarly characterised in future.

Recent Developments in Hepatic Drug Oxidation Implications for Clinical Pharmacokinetics

Time-dependent inhibition of CYP3A4 often results in clinically significant drug-drug interactions. In the current study, 37 in vivo cases of irreversible inhibition were collated, focusing on macrolides (erythromycin, clarithromycin, and azithromycin) and diltiazem as inhibitors. The interactions included 17 different CYP3A substrates showing up to a 7-fold increase in AUC (13.5% of studies were in the range of potent inhibition). A systematic analysis of the impact of CYP3A4 degradation half-life (mean t1/2deg = 3 days, ranging from 1 to 6 days) on the prediction of the extent of interaction for compounds with a differential contribution from CYP3A4 to the overall elimination (defined by fmCYP3A4) was performed. Although the prediction accuracy was very sensitive to the CYP3A4 degradation rate for substrates mainly eliminated by this enzyme fm(CYP3A4 >or= 0.9), minimal effects are observed when CYP3A4 contributes less than 50% to the overall elimination in cases when the parallel elimination pathway is not subject to inhibition. Use of the mean CYP3A4 t1/2deg (3 days), average unbound systemic plasma concentration of the inhibitor, and the corresponding fm(CYP3A4) resulted in 89% of studies predicted within 2-fold of the in vivo value. The impact of the interaction in the gut wall was assessed by assuming maximal intestinal inhibition of CYP3A4. Although a reduced number of false-negative predictions was observed, there was an increased number of overpredictions, and generally, a loss of prediction accuracy was observed. The impact of the possible interplay between CYP3A4 and efflux transporters on the intestinal interaction requires further evaluation.

Prediction of time-dependent CYP3A4 drug-drug interactions: impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition.

The effects of co-dergocrine on cyclosporin A pharmacokinetics and pharmacodynamics.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.

Cyclosporin-erythromycin interaction in normal subjects.

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The effects of co-dergocrine on cyclosporin A pharmacokinetics and pharmacodynamics.

Cyclosporin-erythromycin interaction in normal subjects.