Accurate arterial input function (AIF) measurement in prostate Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) remains challenging. This hinders DCE-MRI’s wider clinical adoption. Since Gadolinium based contrast reagent (CR) is detected indirectly through water proton R₁ relaxation rate constant change, DCE-MRI is intrinsically a dual-molecular probe (CR and water) technique. In this study, we demonstrate that while the most common pharmacokinetic model parameters like K^trans (CR transfer constant) and v_e (extravascular, extracellular, volume fraction) are highly AIF-dependent for prostate DCE‑MRI, the transcytolemmal water exchange parameter is not. With the recent correlation of water exchange kinetics and cellular metabolic activity, this work demonstrates the practicability of a high-resolution metabolic imaging approach for the prostate. Prostate DCE-MRI data were acquired on 13 subjects with a Siemens TIM Trio (3T) system under an IRB-approved protocol. RF receiving used a combination of Spine Matrix and flexible Body Matrix coil arrays. The DCE-MRI acquisition employed a 3D TurboFLASH pulse sequence with a 256*144*16 matrix size and a 360*203 mm² FOV; slice thickness 3 or 3.2 mm. Imaging parameters are: TR/TE/FA, 5.0 ms/1.57 ms/15º; and image frame sampling interval is 6.3 s. Other details are reported previously.¹ All subjects subsequently underwent standard ultrasound-guided systematic ten-core prostate biopsies. Malignancy was found in 5 subjects. One region of interest (ROI) was selected for each subject, resulting in 5 malignant and 8 benign ROI time-courses.¹ The water exchange pharmacokinetic model assuming a single compartment of water signal² extracts K^trans, v_e, and τ_i (mean intracellular water lifetime) parameters. Monte Carlo simulations were used to investigate parameter changes associated with AIF magnitude variation. The “true” AIF (AIF₀) was that determined directly from the data¹. A noiseless tissue time-course was first generated based on data acquisition detail and pharmacokinetic equations. Simulations then fitted pharmacokinetic parameters to the time-course with various AIF amplitudes scaled from 0.8 to 2.0 of AIF₀ (step-size 0.1). For each amplitude-adjusted AIF (e.g., AIF₁ = 130%∙AIF₀), four hundred fittings were performed with random Gaussian noise added to the simulated time-course and a different initial guess parameter value set each time. The Figure 1 bar graph shows the K^trans, v_e, and τ_i accuracy (mean) and precision (SD) changes responding to a 30% AIF amplitude increase (AIF₁). K^trans = 0.4 min^-1, ve = 0.25, and τ_i = 0.45 s base values were used to generate the simulated tissue DCE time-course. K^trans and v_e numerical values decreased nearly 30% with a 30% AIF magnitude increase, while the change for τ_i remains negligibly small (< 3%). The τ_i reciprocal (τ_i^-1) is the unidirectional rate constant for equilibrium cellular water efflux (k_io).⁴ Figure 2a shows a portion of an axial T₂-weighted pelvic image (anterior up) of a 66 year old subject with left prostate malignancy. Figures 2b – 2d show zoomed parametric maps of a tumor-encompassing ROI in the left prostate indicated by the 2a yellow rectangle. In Figure 3 lesion ROI-averaged in vivo k_io values are plotted against subsequently obtained ex vivo Gleason scores, for the five malignant cases. A clear trend of increasing k_io with Gleason score (Spearman’s correlation coefficient, r = 0.908; p = 0.0333) is observed (the blue dashed curve is intended only to guide the eye). The error bars show k_io standard errors and estimated Gleason score errors.³ Although the AIF is hard to measure accurately from the CR bolus first-pass, an AIF error of less than 30% can be readily managed from the washout phase, taking into account the total blood volume and CR elimination rate. Furthermore, if k_io increases are dominated by increases in the mean Na+,K+-ATPase [NKA] turnover for the cells in the voxel,⁴ this work suggests significant impact and unprecedented insight into prostate tumor progression in vivo. Active trans-membrane water cycling accompanies the continuous, homeostatic active trans-membrane ion and osmolyte cycling enzymatic activity, driven by the membrane P-type ATPase ion pump, constitutively characteristic of a living cell.⁴ Fig. 3 indicates a greater Gleason score correlates with greater mean NKA activity. Taken together, the k_io map shows in vivo high-resolution metabolic imaging that is insensitive to AIF uncertainty (thus easy to quantify in that sense). It is important to point out that precision in the k_io map is greatest when CR extravasation is extensive (large K^trans),⁴ as always seen in prostate.¹