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Imaging the impact of sex and age on OATP function in humans: Consequences for whole-body pharmacokinetics and liver exposure
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Solène Marieab, c, *, Anne-Lise Lecoqd, Louise Breuila, Fabien Cailléa, Vincent Lebona, Claude Comtata, Sébastien Goutala, Laurent Becquemontd, e, Michel Bottlaendera, Céline Verstuyfte, f, Nicolas Tourniera, *
Acta Pharmaceutica Sinica B | 2025, 15(5) : 2736 - 2745
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Acta Pharmaceutica Sinica B | 2025, 15(5): 2736-2745
• ORIGINAL ARTICLES •
Imaging the impact of sex and age on OATP function in humans: Consequences for whole-body pharmacokinetics and liver exposure
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Solène Marieab, c, *, Anne-Lise Lecoqd, Louise Breuila, Fabien Cailléa, Vincent Lebona, Claude Comtata, Sébastien Goutala, Laurent Becquemontd, e, Michel Bottlaendera, Céline Verstuyfte, f, Nicolas Tourniera, *
Affiliations
  • aUniversité Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Frédéric Joliot, Orsay 91401, France
  • bDépartement de Pharmacie Clinique, Faculté de Pharmacie, Université Paris-Saclay, Orsay 91400, France
  • cAP-HP. Université Paris-Saclay, Hôpital Bicêtre, Pharmacie Clinique, Le Kremlin Bicêtre 94270, France
  • dAP-HP. Université Paris-Saclay, Hôpital Bicêtre, Centre de Recherche Clinique, Le Kremlin Bicêtre 94270, France
  • eCESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Univ Paris-Saclay, Le Kremlin Bicêtre F-94275, France
  • fAP-HP. Université Paris-Saclay, Hôpital Bicêtre, Service de génétique Moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin Bicêtre 94270, France
About Author:

E-mail addresses: (Solène Marie),

(Nicolas Tournier).

Author contributions

Solène Marie: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Anne-Lise Lecoq: Writing – review & editing, Validation, Resources, Project administration, Investigation, Data curation. Louise Breuil: Writing – review & editing, Methodology, Formal analysis, Data curation. Fabien Caillé: Writing – review & editing, Resources, Methodology. Vincent Lebon: Writing – review & editing, Resources, Methodology, Investigation, Funding acquisition. Claude Comtat: Writing – review & editing, Visualization, Software, Formal analysis, Data curation. Sébastien Goutal: Writing – review & editing, Visualization, Resources, Formal analysis, Data curation. Laurent Becquemont: Writing – review & editing, Validation, Project administration, Methodology, Investigation, Data curation, Conceptualization. Michel Bottlaender: Writing – review & editing, Visualization, Validation, Methodology, Investigation, Conceptualization. Céline Verstuyft: Writing – review & editing, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Nicolas Tournier: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

doi: 10.1016/j.apsb.2025.03.030
Outline
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Organic anion-transporting polypeptides (OATP) transporter function, which mediates many drugs' liver uptake, was investigated as a molecular determinant of pharmacokinetic variability. Whole-body PET imaging using 11C-glyburide, a metabolically stable OATP probe, was performed in 16 healthy humans. Ten subjects underwent another 11C-glyburide PET acquisition after OATP inhibition using rifampicin. Subjects were sorted according to age and sex: males<30y (24.0 ± 3.2 y, n = 7), males>50y (57.5 ± 5.6 y, n = 4), and females>50y (60.6 ± 2.4 y, n = 5). The blood-to-liver transfer rate (kuptake) was estimated to describe OATP function. Rifampicin decreased kuptake (−73 ± 13%, P < 0.001) and liver exposure (−50 ± 10%, P < 0.001) while increasing exposure in blood (+24 ± 24%, P < 0.01), myocardium, spleen, and brain (P < 0.05). No evidence of extra-hepatic rifampicin-inhibitable transport of 11C-glyburide was found. Baseline liver exposure was 42.6 ± 18.4% higher (P < 0.05) in females>50y compared with males>50 y, consistent with higher kuptake values (P < 0.05), with negligible impact on blood exposure (P < 0.05). In males, neither liver exposure, blood exposure, nor kuptake were affected by aging (P < 0.05). kuptake was positively and negatively correlated with liver (P < 0.01, R2 = 0.78) and blood (P < 0.01, R2 = 0.40) exposures respectively. The impact of OATP function (kuptake) on liver exposure was 4-fold more pronounced than on blood exposure. OATP function may thus drive important sex-related differences in liver exposure, which were not discernible through conventional blood-based pharmacokinetics.

Liver exposure  /  Imaging  /  Drug transporter  /  Drug–drug interaction  /  Drug-induced liver injury  /  Pharmacokinetics  /  Solute carrier  /  Gender
Solène Mariea, Anne-Lise Lecoq, Louise Breuil, Fabien Caillé, Vincent Lebon, Claude Comtat, Sébastien Goutal, Laurent Becquemont, Michel Bottlaender, Céline Verstuyft, Nicolas Tournier. Imaging the impact of sex and age on OATP function in humans: Consequences for whole-body pharmacokinetics and liver exposure[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (5) : 2736 -2745 . DOI: 10.1016/j.apsb.2025.03.030
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1.　Introduction
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Population characteristics such as sex and aging may be associated with clinically significant differences in pharmacokinetics (PK), with consequences for drug efficacy and safety1. Such pharmacokinetic variability is often observed at the latest stages of drug development and even once the investigated drug is on the market. Anticipating pharmacokinetic variability may help optimize dose regimens to improve drug efficacy and tolerance in the targeted populations. However, in most situations, the molecular determinants leading to PK variability associated with sex or aging remain largely unknown2,3. In this context, sex- or aging-related differences in the function of most known drug transporters remain to be clarified in humans4,5.
Transporters of the organic anion-transporting polypeptides family (OATP), also known as Solute Carrier (SLCO) transporters, are considered important for PK6,7. In particular, OATPs expressed by hepatocytes (OATP1B1, OATP1B3, and OATP2B1) are known to play a key role in the hepatobiliary elimination of many drugs by mediating their uptake by hepatocytes8,9. Inhibition of liver OATPs is associated with decreased hepatobiliary clearance and may lead to clinically significant drug–drug interactions (DDIs) between OATP substrates and inhibitors6. Studies have also demonstrated a clinically significant decrease in the clearance of OATP substrates such as statins, repaglinide, atrasentan, irinotecan, and many others6,10. Polymorphisms of SLCO genes, especially OATP1B1, were associated with this decrease; these results hold potentially significant consequences for toxicity11. Some studies have focused on potential changes in OATP expression associated with sex and aging in liver samples from animals or humans5,12—14. It may nonetheless be hypothesized that changes in OATP function may account for the observed sex- or age-related PK variability in humans.
Clinical pharmacokinetic studies indirectly estimate the impact of changes in OATP function through changes in the plasma kinetics of the substrate drugs 4,15. However, this approach cannot accurately predict the extent of changes in OATP function at the blood-liver level. Additionally, from a drug efficacy or toxicity perspective, the target tissue concentration rather than plasma concentration is the most relevant. Unfortunately, changes in plasma exposure cannot accurately predict changes in exposure of target/vulnerable organs 16. This unknown particularly holds for liver exposure which may lead to drug-induced liver injury (DILI) 17.
Hepatic OATP function can be non-invasively and quantitatively studied through 11C-glyburide, a recently developed positron emission tomography (PET) probe18,19. 11C-glyburide is predominantly transported by OATP1B1, which mediates its uptake from the blood to the liver20,21. The clinical validation of 11C-glyburide as a PET probe for OATP, conducted in healthy young males, showed its specificity and suitable sensitivity to detect changes in liver transport function 18.
This study conducted whole-body dynamic (WB-4D) PET-MR (magnetic resonance) experiments using 11C-glyburide to explore differences in OATP function associated with sex and aging. Liver OATP function and WBPK of 11C-glyburide were compared in healthy males and females (>50y). Data obtained in males >50y were compared to those obtained in younger males (<30y) using the same method. All subjects were assessed for single nucleotide variants (SNVs) of SLCO genes to consider any difference in genetic polymorphism.10
2.　Material and methods
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2.1.　 Subjects and study design
The study protocol was approved by an Ethic Committee (CPP IDF5: 17041, Study registration EudraCT 2017-001703-69). Experiments were conducted with respect to the 1975 Declaration of Helsinki. All subjects had a first medical examination where the inclusion criteria were checked by the clinical investigator. A written informed consent was signed after the subjects received all information about the study. A blood sample was collected for pharmacogenetic analysis, to genotype the SLCO genes encoding for OATP transporters.
Twenty-four volunteers were included in the study. Eight of them could not participate in imaging sessions due to technical issues. The subjects were classified into three groups: males below 30 years old (M < 30 y, 24.0 ± 3.2 y, n = 7), males above 50 years old (M > 50 y, 57.5 ± 5.6 y, n = 4), and post-menopausal females above 50 years old (F > 50 y, 60.6 ± 2.4 y, n = 5), Details about the groups and the subjects are provided in Table 1. Previously reported validation of 11C-glyburide for OATP imaging was performed with the data of the males <30y group 18.
Imaging sessions were held on a single day. Baseline WB-4D PET acquisition started with intravenous (i.v.) bolus of 11C-glyburide. When possible, at least 3 h later after the first acquisition, a second 11C-glyburide WB-4D PET scan was performed after infusion of rifampicin, used as an inhibitor of OATP, as previously described 18 (9 mg/kg diluted in glucose 5% perfused, within 45 min of 11C-glyburide injection, Rifadin®, Sanofi-Aventis, Gentilly, France). Sixteen volunteers underwent a baseline 11C-glyburide WB-4D PET acquisition. Ten of them underwent a second WB-4D PET in the presence of OATP inhibition (n = 5, 1, and 4, respectively for M < 30 y, M > 50 y, and F > 50y).
2.2.　 Candidate genetic polymorphisms analysis
Methods for genotyping SLCO1A2 c.516A > C (rs11568563), SLCO1B1 c.521T > C (rs4149015), SLCO1B3∗4 c.699G > A (rs7311358), SLCO2B1 ex5 c.601G > A (rs35199625), and SLCO2B1 ex10 c.1457C > T (rs2306168) are reported as supporting information.
2.3.　 PET acquisition
Pharmaceutical grade production of 11C-glyburide, obtained using a previously reported method 22, is described as supporting information. WB-4D PET acquisitions were performed using a SIGNA® PET/MR scanner (GE Healthcare, Waukesha, WI, USA). The subjects were positioned on the patient bed, and MR localization acquisitions were performed. One venous catheter was inserted in each arm to inject 11C-glyburide (1 min bolus) and blood sampling, respectively. Blood sampling was performed to i) determine the binding to plasma proteins before 11C-glyburide injection (T = 0) 57 and ii) assess the unchanged fraction of 11C-glyburide in plasma (T = 0, 5, 10, 15, and 30 min after 11C-glyburide injection, supporting information). The mean injected dose of 11C-glyburide for baseline scans was 167 ± 56 MBq and 174 ± 53 MBq for the second scans. The mean specific radioactivity at the time of injection was 9.5 GBq/μmol and the corresponding mass of glyburide injected was 12.5 ± 6.2 μg. PET acquisition started with the injection of 11C-glyburide. The first 3-min dynamic mono-bed acquisition was positioned on the abdomen (16 frames of 10 s), to capture uptake in the liver and some abdominal organs. This acquisition was immediately followed by repeated multi-bed whole-body acquisitions performed over the next 30 min (11 5-bed position acquisitions of 2.5 min, over a whole-body axial field-of-view of 25 cm).
2.4.　 PET data analysis
PET images were reconstructed using a 3D-iterative reconstruction algorithm, including resolution modeling and time-of-flight. Data was corrected for radioactive decay, attenuation, and random and scattered coincidences. Attenuation correction was based on a 2-point Dixon MR sequence (MRAC). Volumes of interest (VOIs) were delineated for tissues (liver, kidneys, spleen, myocardium, pancreas, brain, and muscle) from PET and/or co-registered MRAC images using the PMOD® software (version 3.9, PMOD Technologies LLC, Zurich, Switzerland). An additional VOI was delineated which includes the left ventricle and the aorta to obtain an image-derived input function (IDIF). Validation of this method, performed in subjects of the males <30 y group, has already been reported and demonstrated a good correlation between IDIF and data from arterial blood sampling18. Urinary bladder was not investigated since our preliminary study using 11C-glyburide demonstrated that radioactivity detected in urine almost exclusively corresponded to radiometabolites 18.
Time–activity curves (TACs) were generated by calculating the mean radioactivity in these VOIs (kBq/cc). The TACs were expressed in standardized uptake values (SUV, unitless), generated by correcting the radioactivity in the VOIs for injected dose (kBq) and body weight (g). Areas under the TACs (AUC, expressed in SUV.min) were calculated from 0 to 30 min for each TAC to describe tissue exposure. Ratios between AUC in each tissue and arterial AUC estimated by IDIF (Kp = AUCtissue/AUCblood) were also calculated from 0 to 30 min to estimate tissue distribution.
The transfer constant (kuptake) of 11C-glyburide from blood to the liver was estimated using the integration plot analysis 23,24 from 5 to 30 min after 11C-glyburide injection using Eq. (1):
Cliver,tCblood,t=kuptake×(AUCblood,0−tCblood,t)+VE
where Cliver,t and Cblood,t represent the concentrations of 11C-glyburide in the liver and blood (IDIF) respectively at time t. AUCblood,0–t represents the area under the IDIF TAC from time 0 to t. kuptake corresponds to the slope of the linear regression plot. VE represents the initial distribution volume in the liver at time 0.
2.5.　 Data and statistical analysis
Data is reported as the mean ± SD (standard deviation). Differences between multiple groups were analyzed by a mixed-effect analysis followed by Tukey’s multiple-comparison test. The level of statistical significance was set to a P-value of less than 0.05. Linear regression and statistical comparisons were performed using GraphPad Prism® software (version 10.0, San Diego, CA, USA).
3.　Results
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3.1.　 Subjects and SLCO genotypes
Results of the genotyping of the genes encoding for OATP transporters are presented in Table 1. All subjects were wild-type carriers for the SLCO2B1 ex5 (rs35199625) gene. Allelic variants were identified for all the other tested genes, with a range from one carrier of heterozygous mutation for SLCO2B1 ex10 (rs2306168) to 6 mutated alleles for SLCO1B1 (rs4149015). One subject carrier of the homozygous allelic variant was observed for the SLCO2B1 ex10 (rs2306168, M < 30 y) and SLCO1B1 (rs4149015, F > 50 y) genetic polymorphisms. Regarding the SLCO1B3 (rs7311358, M > 50 y) polymorphism, 11 subjects were carriers of the c.699G > A mutation, which is predominant in Europe25.
3.2.　 Metabolism and binding to plasma protein
11C-glyburide was barely metabolized in both baseline and rifampicin conditions (Supporting Information Fig. S1). In all subjects, regardless of the presence or the absence of rifampicin, parent (unmetabolized) 11C-glyburide accounted for 90% or more of the plasma radioactivity during PET acquisition in the three groups of subjects. It was therefore decided not to correct blood data from radiometabolites given their limited impact on PET quantification. 11C-glyburide was highly bound to plasma proteins with a mean of 99.7 ± 0.6% in baseline condition and 99.3 ± 1.1% in rifampicin condition (Supporting Information Table S1), implying negligible impact of rifampicin on the free fraction of 11C-glyburide in plasma. Blood kinetics could therefore be described by the IDIF for kinetic modeling, as previously validated 18.
3.3.　 Liver and blood data
Representative PET images of the whole-body distribution obtained in each group display the predominant uptake of 11C-glyburide by the liver (Fig. 1). Liver uptake was visually reduced by OATP inhibition. Radioactivity in the circulation was obvious, probably reflecting the binding of 11C-glyburide to plasma proteins.
The TACs presented in Fig. 2 confirm the high uptake of 11C-glyburide by the liver. In baseline conditions, SUVmax liver was 18.8 ± 4.2 for M < 30 y, 16.4 ± 1.8 for M > 50 y, and 23.3 ± 3.2 for F > 50 y. AUCliver was similar in M > 50y compared to M < 30 y (−10.7 ± 8.8%, P > 0.05), suggesting a limited impact of aging on liver exposure (Fig. 3). However, liver exposure was significantly higher in F > 50y compared with age-matched males (M > 50 y, +42.6 ± 18.4%, Fig. 3). Changes in liver exposure did not translate into significant changes in blood exposure neither between M > 50 y versus F > 50 y, nor between M < 30 y and M > 50 y (Figure 2, Figure 3). Significantly, higher liver exposure in females was also found when compared with pooled male data (M < 30 y + M > 50 y, n = 11, P < 0.001, Supporting Information Fig. S2). Only one subject belonging to the F > 50 y group presented the homozygous mutation on the SLCO1B1 gene (Table 1). She differed from the rest of the group in terms of blood exposure (AUCblood = 340 SUV.min vs 212 ± 26 SUV.min for the rest of the group, Fig. 3, Table S1) but not for the liver exposure (AUCliver = 544 SUV.min vs 572 ± 83 SUV.min for the rest of the group, Fig. 3, Table S1). Such behavior was not observed for subjects with either homozygous mutations of the SLCO1B3 (M > 50 y group), SLCO2B1 (M < 30 y group) genes, or heterozygous mutations of the investigated genes.
OATP inhibition using rifampicin drastically decreased liver exposure of 11C-glyburide in all studied groups (−50 ± 10%, P < 0.001, Fig. 3, Table S1), which translated into a significant increase in blood exposure (+24 ± 24%, P < 0.01, Fig. 3, Table S1). This trend was similarly observed across study groups. In the presence of rifampicin, levels of liver exposure were not different across study groups (P > 0.05, Fig. S2).
The kuptake, which describes the blood-to-liver transfer of 11C-glyburide, was significantly decreased by rifampicin (Fig. 3). The global magnitude of decrease in kuptake was −73 ± 13% (P < 0.001, n = 10). Low and similar kuptake values were obtained in the presence of rifampicin, with no significant difference between groups (P > 0.05, Fig. 3). Mean baseline kuptake in F > 50y (n = 5) was 45 ± 42% higher than that of M > 50 y, although non-significant when considering the entire group (n = 5, Fig. 3). However, statistical significance was reached (+60 ± 28%, P < 0.05, n = 4) when removing the subject with the homozygous mutation at the SLCO1B1 gene from the F > 50y group (Fig. 3). This result was confirmed when pooling together the male data (P < 0.05, Fig. S2). Importantly, the magnitude of decreased kuptake induced by rifampicin was strongly correlated with baseline kuptake (P < 0.001, R2 = 0.95, Supporting Information Fig. S3), consistent with the negligible kuptake values of 11C-glyburide in the presence of OATP inhibition.
When considering subjects of all 3 groups, in the presence and the absence of rifampicin, a significant and positive correlation was observed between kuptake and the liver exposure (P < 0.01, R2 = 0.78, slope = 3937 SUV.min2, Fig. 4). A negative correlation was also observed between kuptake and blood exposure (P < 0.01, R2 = 0.40, slope = −1036 SUV.min2, Fig. 4). This shows that OATP-mediated uptake governs both liver and blood exposures. However, the impact of OATP-mediated transport on liver exposure was ∼4-fold higher than that on blood exposure.
3.4.　 WBPK of 11C-glyburide
The kuptake could not be reliably estimated for most organs except the liver, probably due to low or extremely rapid uptake by these organs. The WBPK of 11C-glyburide was therefore described by the tissue/plasma ratio (Kp,tissue = AUCtissue/AUCblood). In addition to the liver (Kp = 2.26 ± 0.23, Fig. 3), substantial uptake of 11C-glyburide was observed in the kidneys (Kp = 0.97 ± 0.06), pancreas (Kp = 0.67 ± 0.09), myocardium (Kp = 0.51 ± 0.02), and spleen (Kp = 0.45 ± 0.04) (Fig. 5).
Consistent with liver kuptake values, rifampicin significantly decreased Kp,liver (Fig. 3, Table S1). However, rifampicin did not impact Kp in any other organ than the liver, suggesting the absence or limited impact of rifampicin-inhibitable transport (Fig. 5, Table S1). As a consequence of increased blood exposure (AUCblood), rifampicin significantly increased tissue exposure (AUCtissue) in some organs including the myocardium (P < 0.05), spleen (P < 0.05) and brain (P < 0.001, n = 10, Supporting Information Fig. S4).
4.　Discussion
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This study, performed in a cohort of healthy subjects of different sex and age, confirms that 11C-glyburide benefits from metabolic stability, in either the presence or the absence of rifampicin18. In vitro hepatocyte experiments have shown that OATP-mediated uptake (predominantly by OATP1B1) accounts for 98% of the total liver uptake of glyburide, so the estimated proportion of metabolites in the liver is <10% 26. Different studies have also reported a higher affinity of glyburide for OATP1B1, with the lowest Km (1.2–2.0 μmol/L), compared to other OATPs (15–17 μmol/L and 6.3 μmol/L for OATP1B3 and OATP2B1 respectively) 27. More recently, it was estimated that OATP function accounts for 82% of the total liver uptake of glyburide (45% by OATP1B1, 26% by OATP1B3, and 11% by OATP2B1) using the proteomics-informed relative expression factor approach 21. These results suggest that the PET signal predominantly reflects the parent (unmetabolized) compound so that the blood-to-liver transfer (kuptake) can be reliably estimated for 11C-glyburide, which is a major asset compared with previous PET probes24,28,29. The dramatic decrease in kuptake precipitated by the OATP inhibitor rifampicin supports both the sensitivity of 11C-glyburide to detect changes in OATP function and its specificity for OATP.
The strong correlation between individual kuptake values and corresponding liver or blood exposure suggests that liver OATP function, which occurs at the sinusoidal pole of hepatocytes 7, governs both the liver exposure and peripheral kinetics of 11C-glyburide as a rate-determining factor. Therefore, our imaging data supports the relevance of the “extended clearance concept,” which assumes that the transmembrane permeation process in elimination organs may predict the overall clearance of drugs 30. Notably, the impact of change in kuptake on liver exposure was ∼4-fold more pronounced than that on blood exposure. This result illustrates that estimation of OATP function by considering blood concentration of endogenous or exogenous probe substrates only 4,31 may considerably underestimate the impact of these transporters on liver exposure.
Two factors of variability in OATP function were investigated in this study. The most important result is the higher liver exposure observed in females compared with age-matched males after injection of the same dose of 11C-glyburide. Higher liver exposure was linked to higher OATP function, as estimated by kuptake. This outcome points to sex differences in liver exposure to drugs as a consequence of sex-related differences in OATP function. This in vivo result is consistent with the 1.3-fold higher expression of the SLCO1B1 gene in females, measured in human samples 5,13. However, previous proteomic studies based on human liver samples obtained from a large cohort, did not show a significantly higher abundance of OATP1B1 in females compared with males, although considerable variability was observed 32,33. Western-blot analysis has previously revealed a trend toward a higher abundance of liver OATP transporters in females vs males. This cohort better matched the population of our study (56 ± 12 y, 7 males, 10 females), however, this trend was not statistically significant34.
Our results suggest that sex-biased OATP function, which drives higher liver exposure in females, may account for the higher prevalence of DILI in females35,36. It was shown that females have a 1.5- to 1.7-fold greater risk of developing DILI and the female/male ratio increases after the age of 49 years, suggesting a higher susceptibility to DILI after menopause37. Unfortunately, 11C-glyburide was not performed in young females for sex comparison in the young population.
Importantly, sex-related differences in OATP function—as well as liver exposure—could not be predicted from blood kinetics of 11C-glyburide, even when excluding the subject with the homologous mutation of the SLCO1B1 gene that shows particularly high baseline blood exposure compared with the rest of the group. Indeed, changes in blood exposure to 11C-glyburide drastically underestimated changes in liver exposure. This observation is consistent with PK studies performed in larger cohorts that did not report any change in blood kinetics of glyburide between healthy males and females >60 y38. Neither was the plasma kinetics of pravastatin, another OATP1B1 substrate, different between males and females 39—41.
Aging is the second factor of variability investigated in this study. The impact of normal aging on liver structure and function is well known, with a significant decrease in total liver volume, blood flow, and vascular volume42. The impact of age-related decline in renal function on drug clearance is also well established and allows for dose optimization in elderly patients43. In contrast, the impact of aging on liver transport and metabolism remains unclear 43,44. Our results do not support any significant impact of aging on liver OATP function, at least in males. Studies comparing the impact of aging on the plasma PK of OATP substrates are often inconclusive due to the frequent involvement of several other elimination pathways4. Ex vivo studies using proteomic or western-blot analysis reported no correlation between age and the abundance of OATP transporters32—34. We also found a limited impact of aging on blood or liver exposure to 11C-glyburide, which is consistent with previous studies showing no or limited impact of aging on blood exposure to orally administered glyburide in either healthy subjects38 or patients with type 2 diabetes45. One of these studies reported a slower absorption in older subjects; however, the absorption phase could not be investigated in our study because 11C-glyburide was i.v. administered. Moreover, studies reported a negligible impact of aging on the disposition of the OATP1B1 substrate pravastatin in the plasma of healthy subjects so dose adjustment in the older population is not required for this drug40,41.
The liver perfusion of subjects included in this study has not been measured. However, age-related decline in liver perfusion is well established46. Our results suggest that OATP function remains unaltered as the main parameter governing the hepatobiliary elimination of 11C-glyburide in older males. This finding suggests that OATP-mediated elimination of 11C-glyburide does not depend on liver blood flow or perfusion. From a PET imaging perspective, this may suggest that flow-limited passive diffusion of 11C-glyburide, which can be estimated in the presence of rifampicin, has limited importance on the estimation of OATP function using this PET probe. Unfortunately, only one M > 50y underwent a second PET scan after complete OATP inhibition. However, the kuptake value for this subject was similar to that observed in the F > 50 y and M < 30 y groups.
The use of WB-4D PET acquisition enabled the study of WBPK of 11C-glyburide. Imaging data shows a relatively low uptake of 11C-glyburide in organs other than the liver. This low signal did not enable accurate quantification of 11C-glyburide in some organs of small size, such as testis (data not shown). Importantly, the Kp of 11C-glyburide was not decreased in any investigated organ except the liver. This result suggests a liver-specific transport for this probe, consistent with the prime importance of OATP1B1, a liver-specific isoform, in mediating its transport. As a consequence, 11C-glyburide may lack sensitivity and/or specificity to detect extrahepatic OATP function mediated by OATP2B1 or OATP1A2, whose expression has been detected in other organs9. OATP inhibition increased the disposition of 11C-glyburide in some organs as a result of enhanced blood exposure due to decreased liver uptake. Altogether, this PET data convincingly illustrates the impact of OATP-mediated DDI on WBPK in humans.
Some limitations exist in this study. Compared with traditional PK studies focusing on blood data, the total number of scanned subjects (n = 16 baseline scan, 10 rifampicin scan) is relatively small. This number, nonetheless, is higher than in previous PET imaging studies focusing on liver drug transporters 24,47—49. Rifampicin scans could not be performed in all the subjects, with only one rifampicin scan in the M > 50y group. Data obtained from 10 subjects belonging to the different groups who underwent both the baseline and post-rifampicin scans was amply sufficient to show the impact of rifampicin on liver function and WBPK. These results validate 11C-glyburide PET imaging as a probe for OATP function. For most probes, drug transporter function is estimated by the magnitude of response to complete inhibition which requires two subsequent PET acquisitions28,50. However, the strong correlation between the baseline kuptake and rifampicin-precipitated decrease in kuptake suggests that a single baseline 11C-glyburide PET scan is sufficient to estimate the total transport capacity of OATP, as previously reported 18 (Fig. S3). Our sample size (n = 4–7 subjects per group) was sufficient to reveal significant sex-related differences of significant pharmacokinetic importance in liver OATP function and exposure.
The impact of aging on OATP function was only investigated in males because females <30 y were not included. Hormonal regulation of OATPs has been reported 51,52. The importance of hormonal changes during the menstrual cycle for pharmacokinetic variability should be considered 53. This consideration may complicate the interpretation of 11C-glyburide PET data in pre-menopausal females. Moreover, effective contraception, which may also impact OATP function, is required to conduct PET studies in women of childbearing age. For these reasons, only post-menopausal women were included in our study. It should be noted that sex-related differences in OATP function and liver exposure were found in subjects >50 y, who correspond to the most medicated population, with an increased risk of DDI 54.
PET studies using dedicated probes may help untangle the pharmacokinetic importance of the genetic polymorphism of SLCO genes whose impact on transporter function has been reported27,55. Our study was not designed to address the impact of genetic polymorphism on OATP function using 11C-glyburide PET imaging. Only one subject carrier of the well-characterized SLCO1B1 no-function homozygous variant c.521 T > C (rs4149056) was scanned and differed from the rest of the group (F > 50 y). Other SLCO1B3 and SLCO2B1 genetic polymorphisms did not have such an effect in our cohort. However, 11C-glyburide may lack the sensitivity to detect changes in OATP1B3 or OATP2B1 function, given its predominant transport by OATP1B1 26. Polymorphisms on the SLCO1B1 gene have been classified as highly significant for PK by the International Transporter Consortium56. Our data suggests that this polymorphism may have dramatic consequences for liver exposure. Further studies using 11C-glyburide PET imaging, including a larger number of subjects selected upon SLCO1B1 gene polymorphism, should be performed to quantitatively address the impact of this SNV on OATP function and the WBPK using 11C-glyburide PET imaging. Our results suggest that genetic polymorphism should be investigated separately in males and females.
5.　Conclusions
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WB-4D PET imaging revealed the tissue kinetics of 11C-glyburide in humans. OATP inhibition using rifampicin showed the prime importance of hepatocyte OATP function in controlling liver and blood exposure, with consequences for WBPK. Our results suggest no significant decline in OATP function with aging. However, dramatically higher liver exposure was observed in females >50y compared with age-matched males, which was linked with greater OATP function. This sex difference was not discernible through conventional blood-based pharmacokinetics.
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Appendix
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Year 2025 volume 15 Issue 5
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Article Info
doi: 10.1016/j.apsb.2025.03.030
  • Receive Date：2024-09-18
  • Online Date：2026-09-17
Article Data
Affiliations
History
  • Received：2024-09-18
  • Revised：2024-12-28
  • Accepted：2025-01-15
Affiliations
    aUniversité Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Frédéric Joliot, Orsay 91401, France
    bDépartement de Pharmacie Clinique, Faculté de Pharmacie, Université Paris-Saclay, Orsay 91400, France
    cAP-HP. Université Paris-Saclay, Hôpital Bicêtre, Pharmacie Clinique, Le Kremlin Bicêtre 94270, France
    dAP-HP. Université Paris-Saclay, Hôpital Bicêtre, Centre de Recherche Clinique, Le Kremlin Bicêtre 94270, France
    eCESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Univ Paris-Saclay, Le Kremlin Bicêtre F-94275, France
    fAP-HP. Université Paris-Saclay, Hôpital Bicêtre, Service de génétique Moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin Bicêtre 94270, France

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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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