Hunner Lesion Obeys Michaelis-Menten Kinetics In Delaying The Elimination of Drugs

Tyagi P1, Ganguly A1, Yoshimura N1, Jonathan K2, Chancellor M2, Chermansky C1

Research Type

Clinical

Abstract Category

Pharmacology

Abstract 653
Open Discussion ePosters
Scientific Open Discussion Session 33
Friday 29th September 2023
12:40 - 12:45 (ePoster Station 5)
Exhibit Hall
Painful Bladder Syndrome/Interstitial Cystitis (IC) Pharmacology Biochemistry Pain, other
1. University of Pittsburgh, 2. Lipella Pharmaceuticals
Presenter
P

Pradeep Tyagi

Links

Poster

Abstract

Hypothesis / aims of study
The simple pharmacology of lidocaine propels its use for diagnostic and therapeutic purposes in urology. The intravesical absorption of lidocaine conforms to Henderson Hasselbalch equation as alkaline pH accelerates absorption which is shown to amplify the relief of pain from intradetrusor injection at 5min (ref.1). However, no plausible explanation exists for reconciling the comparable time to peak plasma concentration (Cmax) or similar rate of rise in the lidocaine serum concentration (upslope) between interstitial cystitis/painful bladder pain syndrome (IC/BPS) and healthy control subjects accompanied by a significant difference in the renal elimination of lidocaine in two cohorts. Lidocaine is not the first drug to exhibit delayed elimination in IC/BPS patients as similar phenomena is also noted with the orally ingested fluorescein (ref.2) and with instilled and injected salicylate in evoked cystitis of animals (ref.3). These observations question the assumption of bladder as a non-returning (one-way traffic) compartment for drugs excreted into urine. Here, we distilled the published clinical evidence to test the assumption and to propose a new paradigm for the concentration dependent biphasic impact of Hunner lesion on renal elimination and intravesical absorption of lidocaine and other drugs.
Study design, materials and methods
Published clinical studies on IC/BPS and healthy controls were analyzed to examine the impact of Hunner lesion on intravesical absorption and renal elimination of lidocaine, fluorescein and salicylate. We also explored Michaelis-Menten kinetics as a paradigm to explain the differential impact of Hunner lesion on absorption at instilled concentration and reabsorption at low urine concentration.
Results
The instillation of 2% alkalinized lidocaine in healthy controls and IC/BPS patients generated an overlap in the published Cmax range of 0.66 - 1.71 mg/L (7.2micromolar) and 0.2 to 2.0 mg/L (8.5 micromolar), respectively at Tmax ~30min(ref.1). The overlap is consistent with the equivalence in the upslopes denoting the comparable absorption rate constant (Ka) before Cmax in stark contrast to the significant differences in the downslope post Cmax between IC/BPS patients and healthy controls (Fig.1). The graph depicts slower elimination rate constant (Ke) of -0.082h-1 in IC/BPS patients relative to -0.380 h-1  in healthy volunteers alludes to the accentuated reabsorption of lidocaine excreted in urine of IC/BPS patients by Hunner lesions. Since instilled concentration of lidocaine in lumen is thousand-fold higher than lidocaine concentration measured in urine, we posit that the differential impact of Hunner lesion on Ka and Ke conforms to Michaelis-Menten kinetics as illustrated in Figure 1. Since renal elimination is the primary mode of elimination for lidocaine, reabsorption from bladder is only viable explanation for delayed elimination, as IC/BPS does not impact the rate of urine production. The return of lidocaine, fluorescein and salicylate from urine stored in bladder is not visible in control subjects and animals, but Hunner lesion of IC/BPS subjects accelerated the return of significant amounts of fluorescein back to serum from urine in bladder at 4 to 10 hours after fluorescein ingestion, and for the entire 24 hours after oral intake.
Interpretation of results
Since umbrella cells covering 70% of bladder luminal surface are renowned for their transcellular impermeability, the transcellular absorption of fluorescein (ref.2), lidocaine (ref.1) and salicylate (ref.3) is unlikely and these drugs are exclusively absorbed and reabsorbed across tight junctions of umbrella cells, covering ~30% of luminal surface. Therefore, to explain significant differences in elimination of lidocaine between controls and IC/BPS subjects (Figure 1), we must adopt the paradigm of Michaelis-Menten kinetics and conceptualize the limited number of tight junctions as enzymes or entry points of paracellular diffusion of lidocaine (ref.1) and fluorescein (ref.2). Accordingly, the maximum rate of entry (Ka) is analogous to the maximum rate of enzyme activity (beyond Vmax) plotted by the asymptote phase in the classical Michaelis-Menten kinetics curve.  The Vmax for paracellular diffusion of lidocaine is reached at the instilled concentration 1-2% w/v lidocaine (45-85mM) and any additional increase in rate from tight junctions widened by inflammation secondary to Hunner lesion remains obscured in the serum plot (Figure 1). In contrast, urine concentration of lidocaine during elimination phase is even lower than the micromolar range displayed in serum plots or urinary lidocaine concentration (<0.01mM) is in the linear phase (below Vmax) of Michaelis-Menten kinetics (Figure 1) which makes it easier to discern the impact of Hunner lesion on the reabsorption rate of lidocaine excreted into urine. Therefore, intravesical absorption (at Vmax) of lidocaine, fluorescein and salicylate depicts Michaelis-Menten absorption, urinary recycling of lidocaine in IC/BPS subjects and of salicylate in cystitis cats (ref.3) conforms to first-order elimination (below Vmax). 
The linear phase of Figure 1 also denotes the First order transfer rate of most drugs from one physiologic space to another, describing the pharmacokinetic processes of absorption, distribution, metabolism, and elimination. Michaelis-Menten kinetics for absorption and elimination of instilled lidocaine in IC/BPS patients are inversion of ethanol as oral absorption of ethanol is First-order (below Vmax) but alcohol intoxication with excessive consumption manifests elimination (at Vmax) owing to Michaelis-Menten elimination kinetics of alcohol. 
Overall, lidocaine reabsorption from stored urine in bladder adds to the growing body of pharmacokinetic evidence arguing against the assumption of bladder as non-returning compartment in body because human bladder is shown to reabsorb following agents from urine: sodium, water, urea, lidocaine, fluorescein, and salicylate as well as other drugs.  Not just higher instilled concentration, even higher volume can obscure the impact of Hunner lesion on the differences in intravesical absorption of permeability probe. A past clinical report increased the instilled volume by  >100mL relative to IC/BPS patients and the resulting bladder distension of healthy controls obscured the impact of Hunner lesion on the Cmax of probe as both healthy controls and IC/BPS absorbed ~ 2% of the instilled dose of radiolabeled probe. (Chelsky et al 1994 J Urol  151, 346-9).  Michaelis-Menten absorption (beyond Vmax) of instilled radio iodinated albumin (100 microcuries in 50mL) may explain the lack of difference in serum levels of radio iodinated albumin between IC/BPS and urinary retention or bladder cancer patients despite inflammation widening the tight junctions for the entry of lanthanum tracer in IC/BPS patients (Eldrup et al 1983 Br J Urol  55, 488-92).  Therefore, to reveal the impact of Hunner lesion on intravesical absorption, instilled volume and concentration should adopt values below Vmax and avoid the dilatation of tight junctions and their saturation, respectively.
Concluding message
Here, we describe that the impact of Hunner lesion is easily discernible on the reabsorption rate of lidocaine from urine than on the absorption rate at instilled concentration (45-85mM) because higher concentration saturates tight junctions (entry ports on bladder luminal surface) to obscure the impact of any widening of tight junctions by inflammation secondary to Hunner lesion, which is revealed at lower serum concentration (<0.01mM).  The differential impact of Hunner lesion on absorption and elimination conforms to the asymptote and linear phase of Michaelis-Menten curve, respectively. While Michaelis-Menten kinetics have been previously used to elucidate the non-linear elimination of alcohol, phenytoin, and paclitaxel, this is the first application of Michaelis-Menten kinetics to explain the delayed clearance of instilled lidocaine in IC/BPS patients.
Figure 1 Lower (linear) concentration reveals impact of Hunner lesion on absorption
References
  1. Tyagi P, Ganguly A, Chermansky C, Tarin TV, Yoshimura N, Maranchie J. Does Large Volume of Distribution of Lidocaine Masks Its Systemic Uptake From Bladder? Am J Clin Exp Urol. 11, 2023.
  2. Buffington, C. A., Woodworth, B. E. Excretion of fluorescein in the urine of women with interstitial cystitis. J Urol, 158: 786, 1997
  3. Gao X, Buffington CA, Au JL. Effect of interstitial cystitis on drug absorption from urinary bladder. J Pharmacol Exp Ther. 1994 ;271(2):818-23
Disclosures
Funding DK108937 Clinical Trial No Subjects None
05/07/2024 21:04:06