Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure.

PURPOSE: SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan. METHODS: We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry. RESULTS: Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1. CONCLUSION: The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.

Effects of proton pump inhibitors, esomeprazole and vonoprazan, on the disposition of proguanil, a CYP2C19 substrate, in healthy volunteers.

AIMS: Vonoprazan, a new class of potassium-competitive proton pump inhibitors has been found to attenuate the antiplatelet function of clopidogrel in a recent clinical study, despite weak in vitro activity against CYP2C19. To elucidate the mechanism of this interaction, the present study investigated the effects of esomeprazole and vonoprazan on the pharmacokinetics of proguanil, a CYP2C19 substrate. METHODS: Seven healthy male volunteers (CYP2C19 extensive metabolizers) received a single oral administration of 100 mg proguanil/250 mg atovaquone (control phase), oral esomeprazole (20 mg) for 5 days followed by proguanil/atovaquone (esomeprazole phase) and oral vonoprazan (20 mg) for 5 days followed by proguanil/atovaquone (vonoprazan phase). Concentrations of proguanil and its metabolite, cycloguanil, in plasma and urine in each phase were determined using liquid chromatography-tandem mass spectrometry. RESULTS: Coadministration with proton pump inhibitors resulted in increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively, significantly reducing their AUC ratio (cycloguanil/proguanil) to 0.317-fold (95% confidence interval [CI] 0.256-0.379) and 0.507-fold (95% CI 0.409-0.605) in esomeprazole phase and vonoprazan phase, respectively. Esomeprazole and vonoprazan also significantly reduced the apparent formation clearance (cumulative amount of cycloguanil in urine divided by AUC of proguanil) to 0.324-fold (95% CI 0.212-0.436) and 0.433-fold (95% CI 0.355-0.511), respectively, without significant changes in renal clearance of proguanil and cycloguanil. CONCLUSIONS: Although further studies are needed, both esomeprazole and vonoprazan potentially inhibit CYP2C19 at clinical doses, suggesting caution in the coadministration of these drugs with CYP2C19 substrates.

Analysis of the Change in the Blood Concentration-Time Profile Caused by Complex Drug-Drug Interactions in the Liver Considering the Enterohepatic Circulation: Examining Whether the Inhibition Constants for Uptake, Metabolism, and Biliary Excretion Can be Recovered by the Analyses Using Physiologically Based Pharmacokinetic Modeling.

Hypothetical substrates undergoing transporter-mediated hepatic uptake, metabolism, and enterohepatic circulation with different rate-determining processes with a combination of inhibition constants (Ki) for hepatic uptake, metabolism, and biliary excretion processes were generated with a constant Ki for uptake and incorporated into a physiologically based pharmacokinetic model. Analyses of the kinetic model suggested that the fraction of substrates excreted in the bile to the total elimination by the liver (fbile) can be estimated under certain conditions from kinetic analyses of their blood concentration-time profiles. Using the generated time profiles of substrates with and without coadministration of inhibitors, various pharmacokinetic parameters involving fbile and Ki for the hepatic uptake, metabolism, and biliary excretion of drugs were back-calculated by fitting. Comparing parameters obtained with the original parameter sets by fitting, the Ki were found to be well estimated under the following conditions: the initial estimates for inhibition constants were relatively good, which corresponds to the case for obtaining reliable in vitro inhibition constants. In conclusion, the integration of top-down analyses with bottom-up estimates (experimental determination) of inhibition constants can be used to estimate in vivo inhibition constants and fbile reliably.