This is the first detailed scientific analysis of lidocaine absorption in the bladder that precedes the rapid onset of hypotensive effect within 2 minutes of lidocaine instillation in spinal cord injured patients (ref.1).  Lidocaine is also mixed with heparin as a cocktail to manage the recalcitrant symptoms of Painful Bladder Syndrome/Interstitial Cystitis (IC) patients and the evidence-based recommendation for off-label bladder instillation of Lidocaine and Heparin is backed by evidence grade B and C, respectively.  While the water solubility of heparin and lidocaine allows easy mixing into a cocktail for a single bladder instillation, a huge disparity in their systemic uptake (Table 1) sheds light on the importance of pharmacokinetics for understanding the divergence in the therapeutic mechanism of action.  Here, we deduced the scientific basis for the disparity in the systemic uptake of heparin and lidocaine using standard equations of pharmacology textbooks to underline that divergence in the systemic uptake of heparin and lidocaine is predicated on the asymmetry of molecular weight, hydrodynamic diameter, polarity, and volume of distribution (Vd).

Using model-independent pharmacokinetic equations, we analyzed the serum levels reported after bladder instillation in human subjects (ref.1-3) and then determined the extent of their systemic dilution using Vd measured after intravenous administration of heparin and lidocaine. The divergence in the systemic uptake of instilled lidocaine and heparin was interpreted in light of their physiochemical properties as outlined on the public databases for FDA approved drugs: https://druginfo.nlm.nih.gov/drugportal/ and https://pubchem.ncbi.nlm.nih.gov

Chemically, lidocaine is a synthetic xenobiotic and heparin is an endogenous glycosaminoglycan- a heterogeneous mixture of anionically charged polysaccharide chains with molecular weights ranging from 6 to 20 KiloDaltons (KD) for binding with the clotting factors in the blood. Since the existence of endogenous heparin in mast cells complicates the exact determination of the absorbed dose fraction (F) for instilled heparin, we relied on the reported systemic uptake of the instilled radiopharmaceutical, iodinated albumin (66.5Kd)  in human subjects to estimate the systemic uptake  F= ~0.01% for the instilled heparin dose (Table 1). Compared to lidocaine, passive diffusion of heparin into the intracellular compartment is retarded by its bulkier size as its hydrodynamic diameter of (9+/-1 Angstrom ) is twice of lidocaine (3.95 Angstrom). Furthermore, exclusive residence of absorbed heparin in blood volume reduces the volume of distribution (Vd), and consequently,  heparin Vd mirrors that of the clinical probe used for estimating the blood volume, iodinated albumin. Therefore, heparin Vd normalized to bodyweight is 0.05-0.1 liters/kg equals the estimated blood volume of ~7L for a 70kg adult.   
Since serum levels of heparin are not diluted in any space beyond the blood volume, negligible heparin serum levels accurately reflect its slow diffusion into the bladder wall and poor systemic uptake.  In contrast, the much smaller molecular weight of 234.4 Daltons and hydrodynamic diameter of lidocaine not only facilitates its passive diffusion into the bladder wall but also drive the extensive distribution of absorbed lidocaine into blood volume and extracellular fluid volume as well as the intracellular compartment. As per Henderson–Hasselbalch equation for lidocaine with pKa of 7.8, at normal blood pH of 7.4,  more than 50% of the lidocaine absorbed from the bladder exists in a unionized fraction which readily diffuses across the cell membranes for a reversible binding with the sodium and hyperpolarization-activated cyclic nucleotide-gated channels to achieve a Vd of 0.13-4.5 liters/kg (Table 1). Consquently, the mean Vd of 105L for lidocaine is 15 times higher than heparin Vd in a 70kg adult. Fifteen times larger Vd of Lidocaine provides the context for interpreting the extent of distribution from peak serum levels (Cmax) of 1.06-1.3ug/mL measured at 30min after instillation (5%w/v solution; ref.2) and in 75 other subjects across different studies.  Using standard pharmacokinetic equations, we first calculated the elimination rate constant (ke) = ln(C1/C2)/ (t2 - t1),  where ln is the natural log of C1 and C2 concentrations measured at time points of t1 and t2.  A slower ke of lidocaine than of heparin explains why elimination  half-life (t1/2) of lidocaine = 0.693/ke= 2.02h is slightly longer than t1/2 of 1.5h for heparin. However, larger Vd of lidocaine leads to a ten-fold rise in its systemic clearance (CL) compared to heparin, CL, derived from the product of ke*Vd = -0.343 h-1*105L= 36.01L h-1. Then the product of CL and the area under the curve was divided by the instilled lidocaine dose to compute the systemic uptake for instilled lidocaine or F= 23.4 % which is comparable to the F for instilled oxybutynin measured in a cross-over trial of healthy human volunteers.

Plotted and tabulated results for lidocaine empirically validate the principle that the elimination rate of drugs is independent of the route of administration as the values of pharmacokinetic parameters  (ke, t1/2, CL) for absorbed lidocaine fell within the 95% confidence interval of values reported by other routes. Nearly 8 times higher F for lidocaine instilled in the bladder over lidocaine applied on the skin help us generate the hypothesis that either bladder urothelium is more permeable than skin or the urothelium vasculature is more efficient in clearing drugs absorbed from bladder lumen than the skin vasculature. Glaring differences in the molecular weight and octanol-water partition coefficient (log P) of -19.5 and 1.64 underscore the violation and compliance of heparin and lidocaine, respectively with the Lipinski's Rule of Five for the absorption of drugs across cell membranes: molecular weight < 500, hydrogen bond donors < 5, number of hydrogen acceptors < 5, and log P < 5.  Heparin is also negatively charged with topological polar surface area-area of all polar atoms- nitrogen and oxygen adding up to 652 Å as opposed to just 32.3Å for lidocaine, an amphipathic molecule with pKa of 7.8 capable of generating the unionized fraction for rapid absorption across membranes and extensive distribution (Vd). Vd is a conceptual volume required for diluting the absorbed drug fraction to a concentration equivalent to Cmax. Since absorbed lidocaine gets diluted into Vd, which is approximately 15 times the blood volume, serum lidocaine levels can easily underestimate the true extent of lidocaine absorption. However, instilled lidocaine is known to cause hypotension within 2 minutes of instillation and its propensity for extensive dilution can mask the potential of absorbed lidocaine fraction to precipitate toxicity in vulnerable populations (ref.3).  Moreover, rapid absorption and elimination of lidocaine questions the omission of earlier blood sampling time points while reporting the safety of alkalinized lidocaine in IC patients.

Here, we derived pharmacokinetic data to settle the doubts over systemic uptake of lidocaine instilled in the bladder for localized action, lidocaine absorption is rapid enough to cause a hypotensive effect which is transient because a large Vd of lidocaine accelerates its rapid dilution and clearance (Table 1). Just as asymmetry in the physicochemical properties of heparin and lidocaine explain the discrepancy in their respective serum levels, a similar head to head comparison between systemic uptake of lidocaine instilled in the bladder and equivalent lidocaine dose applied on the skin can not only generate a hypothesis on the relative permeability of skin and urothelium but also shed light on unique vasculature of urothelium which sustains the concentration gradient- the main driving force for passive diffusion of xenobiotics into the bladder.

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