and BUN levels. In rats that have undergone 5/6 nephrectomy, the secretion of cimetidine is markedly reduced, which coincided with lower expression of rMate1 [82]. Similarly, ischemic injury can be accomplished within rats by clamping pedicles for a short period of time and then releasing the clamps and re‐establishing blood flow to the kidneys. This results in ischemic‐reperfusion injury as evidenced by elevations in BUN and serum creatinine levels. In rats that have undergone ischemia‐reperfusion injury, the plasma clearance of the antihistamine famotidine and the probe cation TEA are markedly reduced [83]. Compared with sham‐operated rats, expression of Oct2 and Mate1 proteins were decreased by more than 50% in rats with ischemia‐reperfusion injury [83]. As a result, the impaired clearance is likely due to both diminished uptake by Oct1 and 2 transporters and disrupted efflux by MATE transporters, as well as change in filtration.
Acute kidney injury caused by the cancer drug cisplatin increases BUN and serum creatinine levels and leads to loss of proximal tubules. In rats treated with a toxic dose of cisplatin, there is downregulation of rOct2 and rMate1 protein [84]. Interestingly, the uremic toxin indoxyl sulfate appears to play a role in the reduced levels of both cation transporters as treatment with AST‐120, an adsorbent, partially restored expression of rOct2 and rMate1 protein, as well as improved renal function indicators [84].
3.5.5.2 Liver Disease and Injury
Nonalcoholic fatty liver disease is a prevalent disease in the US patients with advanced disease, or steatohepatitis, often have comorbidities such as type II diabetes and chronic kidney disease. Pathologic features of nonalcoholic steatohepatitis can be recapitulated by feeding rodents a diet deficient in methionine and choline (MCD) or in mice with a genetic predisposition for obesity (known as ob/ob mice). Expression of mOct2 and mMate1 mRNA is reduced in the kidneys of ob/ob mice [85]. Feeding ob/ob mice a MCD diet further lowered expression of mOct2 and mMate1 in the kidneys, which was associated with impaired clearance of metformin. Interestingly, changes in mOct1 or mMate1 mRNA expression were observed in the livers of ob/ob mice regardless of diet [85]. Emerging data from humans with nonalcoholic steatohepatitis or untreated type II diabetes demonstrate hypermethylation of the SLC47A1 gene in liver [86, 87]. These data would tend to support decreased hMATE1 expression as methylation status is a contributor to the interindividual regulation of hMATE1 [88].
3.6 DRUG EFFICACY AND TOXICITY
3.6.1 Clinical Substrates, Probes, and Inhibitors
Several US Food and Drug Administration (FDA) approved drugs have been identified as MATE1 and MATE2‐K substrates. Of those, only metformin is considered a well‐established in vivo MATE substrate for use in clinical interaction studies [89]. By comparison, several inhibitors of MATE1 and MATE2‐K have been recommended for clinical interaction studies, including cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, and vandetanib [89]. An increase in the exposure (area under the plasma concentration‐time curve) in the presence versus absence of a transport inhibitor defines the interaction as strong if ≥5‐fold increase is observed and moderate if a 2‐ to 5‐fold increase is noted [90]. While the FDA does not consider metformin (substrate) or any of the inhibitors as index drugs for prospective drug–drug interaction studies (due to the promiscuity for multiple transporters), clinical interaction studies are advocated to inform about potential interactions during concomitant usage of two drugs. The FDA specifies that if renal secretion accounts for ≥25% of systemic clearance for an investigational drug that has been identified as a MATE substrate from in vitro studies or if there are concerns about kidney toxicity, then a clinical transporter drug–drug interaction study is warranted [90]. Additionally, if an investigational drug is identified as a MATE inhibitor from in vitro studies, then a clinical drug interaction study would incorporate a known substrate that represents the MATE pathway. However, the criteria of the substrate being a likely concomitant drug may not be met in many circumstances.
The drug development process, through preclinical studies, identifies compounds where renal clearance accounts for a significant percentage of the total body clearance. However, since renal clearance can occur through both filtration and secretion, it is important to distinguish the percentage that is accounted for by secretion, in this case by MATE1 or MATE2‐K. The FDA recommends a 25% threshold systemic clearance due to secretion clearance for further evaluation. Additionally, if there is potential nephrotoxicity of a transporter substrate, then drug–drug interactions should be considered since reduced MATE activity could potentiate cellular toxicity. Table 3.3 has collated clearance and exposure data for compounds that are MATE1 and MATE2‐K substrates in humans. Inhibitors of MATE transporters can reduce renal secretory clearance pathway through the relationship of CLsecretion = CLtotal − CLFiltration. The filtration clearance can be estimated by the glomerular filtration rate multiplied by the unbound fraction of the substrate. Highly relevant in Table 3.3 is the expected area under the plasma concentration data for the substrates, as reductions in renal clearance will lead to increased exposures for the substrates and potential toxicities.
3.6.2 Pharmacokinetic Drug Interactions
According to the FDA, if the ratio of unbound drug Cmax concentration divided by the IC50 or K i value for transporter inhibition is ≥0.1, there is potential for an in vivo drug interaction. This section highlights drug interaction studies that have been conducted in humans and evaluated for pharmacokinetic alterations of MATE substrates in the presence of inhibitors (Table 3.4).
3.6.2.1 Metformin
A human drug interaction study was conducted to determine the effect of peficitinib 150 mg (single dose on days 3 and 5–11) (janus kinase inhibitor; rheumatoid arthritis indication) and its metabolite on the pharmacokinetics of metformin (750 mg on Days 1 and 10) [91]. Initial peficitinib in vitro assessments reported an IC50 of 10 μmol/l for MATE1. Expected unbound Cmax concentrations for peficitinib were 0.44 μmol/l. This would result in a Cmax/IC50 quotient of 0.044, suggesting low potential for a clinical interaction. Clinical results showed reduced AUC, Cmax, and renal clearance of metformin with the addition of peficitinib. However, these changes in metformin pharmacokinetics were not considered clinically actionable.
Two studies were conducted to determine whether histamine H2 antagonists impact metformin pharmacokinetics. A study in healthy volunteers (n = 12) evaluated the influence of famotidine (200 mg day 1 and 800 mg day 2), a MATE1 inhibitor, on the pharmacokinetics and pharmacodynamics of metformin [92]. In vitro studies calculated an IC50 of 0.25 μM for famotidine on MATE1, and with an unbound Cmax of 1 μM, a clinical interaction was predicted (Cmax/IC50: 0.25). In the presence of famotidine, a significant increase in metformin exposure and bioavailability and a decrease in renal secretory clearance were demonstrated. The concurrent administration of famotidine also significantly reduced the glucose exposure curve as well as creatinine urinary excretion. The same group of investigators evaluated the effect of nizatidine, a histamine H2 and MATE2‐K inhibitor, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers (n = 12) [93]. In vitro nizatidine has an IC50 of 7.81 μmol/l on MATE2. The unbound Cmax for nizatidine is 2.88 μmol/l suggesting the potential for a drug–drug interaction (Cmax/IC50: 0.37). In the presence of nizatidine, a significant increase in metformin volume of distribution and reduction in the glucose exposure curve, without an impact on renal secretory clearance, was reported.
Abemaciclib is a cyclin‐dependent kinase inhibitor prescribed for the treatment of advanced breast cancer. Measurement of IC50 values for MATE1 (0.52 μM)
