Article Figures & Data
Figures
- Fig. 1.
Localization of OCT3 in human term placenta. Human term placenta sections were colabeled with antibodies for OCT3 (B, F, and J; green) and various membrane markers (C, CD31-PECAM1; G, laminin; K, the transferrin receptor; red). The nuclei were shown in blue (A, E, and I). Merged images are shown in (D, H, and L). Arrow indicates representative staining of fetal capillaries (D) and basal membrane of trophoblasts (H).
- Fig. 2.
Expression of various organic cation transporters in the placentas of Oct3+/+ and Oct3−/− mice. Transcript of various organic cation and monoamine transporters in Oct3+/+ (n = 3) and Oct3−/− (n = 3) mouse placentas at gd 19 was determined by real-time PCR.
- Fig. 3.
Maternal plasma metformin concentration-time profile in pregnant Oct3+/+ (▢) and Oct3−/− mice (■). Pregnant (gd 19) Oct3+/+ (▢) and Oct3−/− (■) mice were given a dose (15 mg/kg) containing 0.2 mCi/kg of [14C]metformin by oral gavage. At various time points (0–480 minutes) after drug administration, animals were sacrificed and blood, tissues, and fetuses were collected. Metformin concentrations in maternal plasma were measured by liquid scintillation counting. Data represent mean ± 1.96 S.E. (n = 3–5 mice/time point). Inset depicts the same data on a semilogarithmic scale.
- Fig. 4.
Fetal metformin concentration-time profile in Oct3+/+ and Oct3−/− mice following oral administration. Pregnant (gd 19) Oct3+/+ (▢) and Oct3−/− (■) mice were given a dose (15 mg/kg) containing 0.2 mCi/kg of [14C]metformin by oral gavage. At various time points (0–480 minutes) after drug administration, animals were euthanized, and blood, tissues, and fetuses were collected. Metformin concentrations in fetus homogenates were determined by liquid scintillation counting. Data represent mean ± 1.96 S.E. (n = 3–5 mice/time point).
- Fig. 5.
Metformin AUC0-480 in various tissues in pregnant Oct3+/+ (▢) and Oct3−/− mice (■). Pregnant (gd 19) Oct3+/+ (▢) and Oct3−/− (■) mice were given a 15 mg/kg metformin dose containing 0.2 mCi/kg of [14C]metformin by oral gavage. At various time points (0–480 minutes) after drug administration, animals were euthanized, and blood, tissues, and fetuses were collected. Metformin concentrations in various maternal tissues were determined and AUC0–480 was calculated as described under Materials and Methods. Data represent mean ± 95% confidence interval. Two-sided P values were calculated using the permutation test as described under Materials and Methods (*P < 0.05).
- Fig. 6.
A proposed model for organic cation transport at the human placenta barrier. Organic cations, such as metformin, in the maternal circulation are first transported into the syncytiotrophoblast cells by NET, SERT, or OCTN2 at the apical membrane. Organic cations are then effluxed down their electrochemical gradient into the fetal side by OCT3 at the basal membrane. Larger and more lipophilic cations can be actively pumped back to the maternal circulation by P-gp and/or BCRP located at the apical membrane. BCRP, breast cancer resistance protein; NET, norepinephrine transporter; OCTN2, organic cation transporter novel type 2; P-gp, P-glycoprotein; SERT, serotonin transporter. This model is based on data in the present study and references (Vähäkangas and Myllynen, 2009; Ganapathy et al., 2000).
Tables
- TABLE 1
Metformin pharmacokinetic parameters from pregnant Oct3+/+ and Oct3−/− mice
Data are presented as mean ± S.E. (Cmax) or with 95% confidence intervals in parentheses.
Oct3+/+ Oct3−/− Cmax (µg/ml) 3.31 ± 0.45 4.17 ± 0.37 AUC0–480min (μg/ml*min) 609 (564, 698) 513 (452, 569)* AUC0–∞ (μg/ml*min) 661 (616, 753) 556 (494, 615) CL/F[(ml/min)/kg] 24.6 (21.5, 26.6) 29.3 (26.4, 33.2) t1/2, β (min) 119 (107, 195) 154 (99.2, 234) Vβ (l/kg) 4.21 (3.60, 7.11) 6.51 (4.23, 10.3) ↵* Significantly different from Oct3+/+ (P < 0.05).
- TABLE 2
Fetal metformin AUC and AUC ratios in Oct3+/+ and Oct3−/− pregnant mice
Data are presented as mean with 95% confidence intervals in parentheses.
Oct3+/+ Oct3−/− % Change AUCfetal, 0–480 min (μg/g*min) 127 (82.6, 146) 77.2 (66.9, 87.4)* 39% AUC0–480 fetal-to-maternal ratio 0.21 (0.14, 0.25) 0.15 (0.13, 0.18)* 29% AUCfetal, 0-∞ (μg/g*min) 181 (136, 204) 95.7 (86.2, 104)* 47% AUC0-∞ fetal-to-maternal ratio 0.27 (0.20, 0.32) 0.17 (0.15, 0.20)* 44% ↵* Significantly different from Oct3+/+ (P < 0.05).
Data Supplement
- Supplemental Figure -
Uptake of [14C]metformin by HEK 293 cells stably expressing hOCT3
- Supplemental Figure -
