Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 25

Hydrophilic drugs can get eliminated in the urine, unchanged. For example, renal elimination is the predominant route for about 60% of anti‐infection compounds (Varma et al., 2009). The fraction of the dose excreted in the urine unchanged (f_e ) is

(1.29)

where A_e,unchanged is the amount of drug excreted in the urine unchanged. Therefore, CL_R is

(1.30)

Figure 1.4. Renal elimination of a drug: glomerular filtration, active tubular secretion, and tubular reabsorption. Lipophilic drugs are readily reabsorbed, making renal elimination an important route only for hydrophilic drugs.

CL_R = f_ub × GFR, where GFR is the glomerular filtration rate, for a drug lacking tubular active secretion or tubular reabsorption (Figure 1.4). GFR reflects passive diffusion of a drug through the glomeruli. Active tubular secretion is evident if CL_R > f_ub × GFR and tubular reabsorption is apparent when CL_R < f_ub × GFR. Reported values of GFR are measured with endogenous filtration markers like creatinine, which is freely filtered and secreted (15%) in the proximal tubule. However, since the synthesis and blood concentration of creatinine are influenced by several factors including age, sex, ethnicity, muscle mass, and chronic illness, other markers such as serum cystatin C, ⁵¹CrEDTA or inulin are employed. Drugs cleared exclusively in the kidney (such as hydrophilic acids and bases with high PSA and rotatable bond count), generally tend to have low rates of renal clearance. This is due to limited glomerular filtration and in some cases, absent active secretion. Apart from low clearances, these compounds are also unaffected by CYP‐related issues such as polymorphisms, drug–drug interaction (DDI) and reactive metabolites.