Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

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.

       1.2.4.4 Biliary Clearance

      Amphiphilic compounds (compounds with both acidic and basic groups), with molecular weights >350 Da also have the possibility of being actively transported into the bile and excreted via faces. Biliary clearance can be estimated by determining the concentration of a drug in the bile (C_bile ) collected from a bile‐duct cannulated preclinical species.

      (1.31)

The parent drug in bile is emptied into the duodenal section of the small intestinal tract via the sphincter of Oddi and may be reabsorbed back into the portal vein as it transits down the intestine. This is called the enterohepatic recirculation (EHR). EHR contributes to an increased half‐life of a drug. Some phase II conjugates are also secreted into bile and converted back to parent in the distal small intestine and reabsorbed as parent.

A metabolite of the drug can also be emptied into bile and into duodenum Figure 1.5. Certain phase II metabolites such as glucuronides are emptied into bile and into duodenum, get reconverted to the parent drug by the gut microflora in the distal intestine and are reabsorbed and recirculated. Although the pharmacokinetic profile is very similar to that associated with parent EHR, the measured C_bile for the parent drug in this case would be low, allowing one to distinguish between parent and metabolite EHR.

1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption

      Other than IV administration, all other routes require the drug to be absorbed into the capillaries that surround the site of administration. The rate of absorption of a drug in solution administered by IM and SC routes is limited by the perfusion to the tissue. It also depends on the type of tissue at the site of administration – the density, vascularity, and the fat content. The IM route for example has higher rate of absorption compared to the SC because of lesser fat and greater vascularity of the dense muscles. The muscle tissue has a greater blood supply than the tissue just under the skin and can hold a larger volume of medication than subcutaneous tissue.

      Oral drug absorption refers to the transport of drug molecules across the enterocytes lining the gastrointestinal (GI) tract into the venous capillaries along the gut wall. The rate of oral drug absorption depends on several physiology‐, drug‐, and formulation‐dependent factors such as gastric emptying rate, intestinal motility, porosity of tight junctions, luminal and mucosal enzymology, carrier and efflux transporters, small‐intestinal secretions (bile and digestive enzymes), regional differences in pH, membrane permeability, solubility, and dissolution rate. An orally absorbed drug is subjected to first pass metabolism in the gut and liver before it is available in systemic circulation.

PK profiles from all extravascular routes are characterized by a maximum systemic concentration (C_max ) and t_max, the time at which the C_max is achieved (Figure 1.6a). Only a fraction of the administered dose is available for systemic circulation. This fraction is called bioavailability (F) of the drug.