Based on blood perfusion, which body compartment will get adequate drug levels more quickly?

Diffusion into Tissues

Diffusion of most antibiotics from plasma to tissues is limited by tissue blood flow, rather than drug lipid solubility. This has been called perfusion rate–limited drug diffusion. If adequate drug concentrations can be achieved in plasma, it is unlikely that a barrier in the tissue will prevent drug diffusion to the site of infection as long as the tissue has an adequate blood supply. In critical care patients, poor perfusion of tissues owing to compromised hemodynamic function could negatively affect this property. Normally, rapid equilibration between extracellular fluid and plasma is possible because of a high ratio of surface area to volume. That is, the surface area of the capillaries is high relative to the volume into which the drug diffuses. Drug diffusion into an abscess or granulation tissue is sometimes a problem because in these conditions drug penetration relies on simple diffusion and the site of infection lacks adequate blood supply. In an abscess, there may not be a physical barrier to diffusion—that is, there is no impenetrable membrane—but low drug concentrations are attained in the abscess or drug is slow to accumulate because in a cavitated lesion there is low ratio of surface area to volume.

In some tissues a lipid membrane (e.g., tight junctions on capillaries) presents a barrier to drug diffusion. This has been called permeability rate–limited drug diffusion. In these instances, a drug must be sufficiently lipid soluble or be actively carried across the membrane to reach effective concentrations in tissues. These tissues include the central nervous system, eye, and prostate. A functional membrane pump (P-glycoprotein) also contributes to the barrier. There also is a barrier between plasma and bronchial epithelium (called the blood-bronchus or blood-alveolar barrier). This limits concentrations of some drugs in the bronchial secretions and epithelial fluid of the airways. Lipophilic drugs may be more likely to diffuse through the blood-bronchus barrier and reach effective drug concentrations in bronchial secretions.

Impaired Diffusion into Tissues

Tissues that lack pores or channels may inhibit penetration of some drugs. In some tissues a lipid membrane (e.g., tight junctions in capillaries) presents a barrier to drug diffusion. In these cases, a drug must be sufficiently lipid soluble or must be actively carried across the membrane to reach effective concentrations in tissues. These tissues include the central nervous system (CNS), eye, and prostate. Lipophilic drugs (e.g., macrolides, fluoroquinolones, tetracyclines, trimethoprim, chloramphenicol) may be more likely to diffuse through lipid membranes for treating infections in these tissues. Many clinicians believe that drug penetration across these barriers is not important when treating inflammatory diseases because these barriers will be breached and drugs will be able to diffuse freely into the affected area. However, this is not always the case. In a study analyzing amikacin concentrations in the CSF of the horse, drug was not detected in any of the horses with a normal blood-brain barrier (BBB).47 In one horse that developed septic meningitis during the study, drug was not detectable until 4 hours after the second injection and reached a peak of only 0.97 µg/mL, which did not occur until 8 hours after the fifth injection.

Box 65-1 summarizes drugs known to penetrate into the cerebrospinal fluid (CSF) and aqueous humor of horses. A barrier also exists between plasma and bronchial epithelium (blood-bronchus barrier).48 This restricts penetration of some drugs in the bronchial secretions and epithelial fluid of the airways. However, disposition of drug into lung tissue not separated by the blood-bronchus barrier is not impaired (e.g., when treating pneumonia).

Diffusion

The following are determinants of rates of diffusion across biologic membranes:

Concentration gradient: The concentration difference across a biologic membrane determines the direction of diffusion (high concentration to low concentration) and its rate (i.e., the rate of diffusion is directly proportional to the concentration difference).

Lipid solubility: Lipophilicity is a term used to describe the solubility of the drug in fatty or oily solutions and is measured by determining the oil/water partition coefficient (P = lipophilicity). The lipophilicity is determined by the number and type of chemical constituents that are attached to the primary chemical molecule (Table 7-1). The oil/water partition coefficient of a drug is a major determinant of the rate of drug diffusion across biologic (lipid/hydrophobic) membranes. The rate of diffusion across a membrane increases linearly with log P up to a maximum value. The optimal value is log P = 0.5 to 2.0.

[Drug]oil :[Drug]waterP=[Drug]oil[Drug]water

Membrane characteristics (anatomic and structural characteristics) and the permeability of different membranes may vary considerably. For example, most capillary membranes are highly permeable, but capillary membranes of the brain contain glial cells that are much less permeable to the diffusion of less lipophilic molecules. (The blood-brain barrier is not a barrier to the diffusion of lipophilic molecules because they readily diffuse through the membrane.) Drugs that have a low molecular weight, are not electrically charged, or are highly lipophilic readily diffuse into the various tissue compartments (e.g., extracellular space, intracellular space, and CSF). The epidural or intrathecal administration of analgesic drugs provides a good example of the practical importance of lipophilicity. Highly lipid-soluble drugs (e.g., fentanyl and oxymorphone) rapidly diffuse out of the epidural space or CSF into surrounding tissues, producing a relatively short duration of analgesic effect. Morphine is less lipid soluble than fentanyl or oxymorphone and therefore produces a much longer duration of analgesia when administered by the epidural route.

Small molecules (e.g., electrolytes, water, and ethanol) appear to diffuse through membranes via aqueous pores. Very large molecules do not readily diffuse through membranes.

21.4.1 Iron oxide nanoparticles

Iron oxide NPs (IONPs) have been investigated for magnetic properties, which find several important applications such as magnetically mediated hyperthermia for cancer treatment [51], contrast agent MRI [52], treatment of anemia [53], etc. However, the recent studies have indicated that the ability of NPs to generate reactive oxygen species (ROS) can be used in cancer therapy [54,55]. Among iron-based NPs, SPIONs are being explored extensively, especially for their therapeutic and diagnostic applications. SPIONs, in particular magnetite (Fe3O4) and maghemite (γ-Fe2O3), are considered as means of transport for targeted drug delivery as they can be guided to the tumor site through an external magnetic field and this prevents drug diffusion to the rest of the body. Due to their superparamagnetic nature, SPIONs lose their magnetism and enter the blood circulation when the external magnetic field ceases [56,57]. The effectiveness of NPs in diagnostic or therapeutic applications can be increased by surface coating, which enhances the physicochemical and biological properties of nanomaterials by providing protection against corrosion and environmental degradation. Also, the biocompatibility and colloidal stability of NPs increases, thereby enhancing the drug release at therapeutic site [58]. N. Mallick et al. [59] have investigated the chondroitin-4-sulphate (CS)-capped SPIONs for loading of the anticancer agent doxorubicin hydrochloride (DOX). The in vitro drug release profile indicated 96.77% of DOX release within 24 hr and MTT assay in MCF7 cells has revealed significantly higher toxicity for CS-SPIONs-DOX with IC50 value 6.294 ± 0.4169. S. Mondal et al. [60] have investigated hydroxyapatite (HAp)-coated IONPs synthesized using solvothermal and chemical precipitation for magnetic hyperthermia-mediated cancer therapy. The nontoxic nature of IONPs-HAp was established by trypan blue and MTT assay. The hyperthermia study performed on osteosarcoma cells (MG-63) displayed excellent hyperthermia effect with specific absorbance rate value 85 W/g. They have achieved hyperthermia temperature of about 45°C within 3 min, which could kill nearly all the studied cancer cells within 30 min. C. Saikia et al. [61] have studied FA-tagged aminated starch/ZnO-coated SPIONs for targeted delivery of anticancer drug, curcumin. The cytotoxicity study of the drug-loaded NPs was analyzed by MTT assay in human lymphocytes, liver cancer cells (HepG2), and MCF7, wherein NPs were found to be compatible with human lymphocyte cells and reduce the cell viability up to 61% with 0.5% ZnO concentration in HepG2 and MCF7 cells. The cell uptake efficiency and ROS generation was studied using HepG2 cell lines. The ROS generation was found to enhance with increasing ZnO concentration in the system. N. Moghadam et al. [62] reported improved antiproliferative effect of the nevirapine (Nev) on cancer cell line (Hela) by loading onto chitosan-coated magnetic iron oxide nanoparticles (MIONPs). The in vitro ct-DNA-binding study has revealed DNA aggregation on Nev-loaded MIONPs through groove-binding mode.

Diffusion

Diffusion across biologic membranes is determined as follows.

Membrane characteristics (anatomic and structural characteristics) and the permeability of different membranes vary considerably. For example, most capillary membranes are highly permeable, but capillary membranes of the brain are much less permeable to the diffusion of less lipophilic molecules. The blood-brain barrier is not a barrier to the diffusion of lipophilic molecules. Drugs that have a low molecular weight, are not electrically charged, or are highly lipophilic readily diffuse into the various tissue compartments (e.g., extracellular space, intracellular space, and CSF).

Concentration gradient: The drug concentration difference across a biologic membrane determines the direction (high concentration to low concentration) and rate (i.e., the rate of diffusion is directly proportional to the concentration difference) of diffusion.

The rate of diffusion of a drug across a membrane depends on the membrane permeability characteristics if the membrane is a barrier to drug passage; this is known as membrane-limited diffusion.

Drugs are delivered rapidly to highly perfused (vessel-rich group) tissues and slowly to poorly perfused (fat group) tissues. The rate of diffusion of a drug across a membrane also depends on its rate of drug delivery to the tissue if the drug rapidly passes through the membrane; this is known as blood-flow rate-limited diffusion.

Lipid solubility: Lipophilicity is a term used to describe the solubility of the drug in fatty or oily solutions and is measured by determining the oil-water partition coefficient (P = lipophilicity). The lipophilicity is determined by the number and type of chemical constituents that are attached to the primary chemical molecule (Table 15-1). The oil-water partition coefficient of a drug is a major determinant of the rate of drug diffusion across biologic (lipid-hydrophobic) membranes.

The ED or intrathecal (IT) administration of analgesic drugs provides a good example of the practical importance of lipophilicity. Highly lipid-soluble drugs (e.g., fentanyl and hydromorphone) rapidly diffuse out of the ED space or CSF into surrounding tissues, producing a relatively short duration of analgesic effect. Morphine is less lipid soluble than fentanyl or hydromorphone and therefore produces a longer duration of analgesia when administered by the ED or IT route.

Small molecules (e.g., electrolytes, water, and ethanol) can diffuse through membranes via aqueous pores. Very large molecules do not readily diffuse through membranes.

Protein binding: Many drugs bind reversibly to macromolecules such as plasma proteins (e.g., albumen, α1-acid glycoprotein) and tissue proteins (Drug + Protein = Drug-protein complex). A bound drug is not free to diffuse or interact with receptors; some active transport processes remove bound drugs from binding sites. Hypoproteinemia can markedly enhance the effect of drugs that are otherwise highly protein bound (e.g., fentanyl, methadone).

Drug protein binding in the blood reduces the concentration of free drug available for diffusion across membranes; therefore the rate of diffusion across the membrane is decreased when a drug is extensively protein bound.

At equilibrium, the concentration of free drug is the same on both sides of the membrane; however, the concentration of the total drug (bound and unbound) may be different on the two sides of the membrane, depending on how much of it is bound to proteins.

Differential ionization: Ionized substances do not diffuse across biologic membranes. Differences in pH exist across many biologic membranes (e.g., the pH of gastric contents ranges from about 2 to 3, and that of plasma is approximately 7.4). These differences lead to accumulation of drug (i.e., ionized plus nonionized) on that side of the membrane where the drug is more ionized.

The partitioning (tissue-to-plasma ratio [RT/P] of a drug between two regions of differing pH) is described by the Henderson-Hasselbalch equation:

RT /P=1+antilogpKa−pHT1+antilogpKa− pHP

Ultrafiltration: Water and relatively small molecules (molecular weight < 500 Da) easily pass through membranes (e.g., glomerular filtration) by the hydrostatic pressure of the blood. Drug molecules bound to plasma proteins are not filtered because most proteins (e.g., albumin: 60 kDa) are generally too large to pass through the membrane.

Carrier-mediated transport: Most membranes possess specialized transport mechanisms that regulate the movement of drugs and other molecules. These transport mechanisms generally use a carrier molecule that may or may not require energy. Carrier-mediated transport is particularly important for the transfer of drugs across the renal tubules, biliary tract, gastrointestinal tract, and blood-brain barrier.

Carrier-mediated transport may or may not limit diffusion but often has a maximum value (becomes saturated). Competitive inhibition of transport may occur if a second molecule binds to the carrier, thereby interfering with the transport of the first molecule.

Active transport is usually coupled to an energy source such as adenosine triphosphate and can transport molecules against an electrochemical gradient (e.g., transport of essential nutrients from the gastrointestinal tract against a concentration gradient). Active transport is usually specific and competitive.

Specificity: The transport mechanism is usually specific for a single substance or a group of closely related substances (e.g., transport of anions from the blood into the renal tubule in the nephron).

Competitive: The transport process is competitively inhibited by other molecules also transported by the system.

Facilitated transport promotes the equilibration of the transported substance—for example, the transport of a molecule in the same direction as its electrochemical gradient (Na+ flux into renal tubules).