Blood-brain barrier ionization

Consequently, many foreign compounds achieve the same concentration in fetal as in maternal plasma. However, if metabolism in utero converts the compound into a more polar metabolite, accumulation may occur in the fetus. Despite extensive blood flow (16% cardiac output 0.5 mLmin 1g 1 of tissue), entry of foreign compounds into the brain takes place much less readily than passage into other tissues. Hence, the term "blood-brain barrier." Ionized compounds will not penetrate the brain in appreciable quantities unless they are carried by active transport systems. The reasons for this are as follows ... 

The exit of drugs from the CNS can involve (1) diffusion across the blood-brain barrier in the reverse direction at rates determined by the lipid solubility and degree of ionization of the drug, (2) drainage from the cerebrospinal fluid (CSP) into the dural blood sinuses by flowing through the wide channels of the arachnoid villi, and (2) active transport of certain organic anions and cations from the CSF to blood across the choroid plexuses... 

Tmovec, T., Z. Kallay, and S. Bezek. 1990. Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances. Inter. Jour. Radiation Oncol. Biol. Physics 19 1581-1587. 

Inflammation, such as occurs in bacterial meningitis or encephalitis, may increase the permeability of the blood-brain barrier, permitting the passage of ionized... 

The Hi-antagonists are classified as either first- or second-generation compounds. Second-generation antihistamines have lipophilicity and ionization profiles that make them less able to cross the blood-brain barrier thus they produce dramatically less sedation than do the first-generation drugs. 

Structural and theoretical chemistry studies of phenytoin and carbamazepine suggest that they bind to the Na+ channel via a pharmacophore that consists of an aromatic ring and an amide linkage. This pharmacophore consists of two of the three structural features found in local anesthetics. The ionizable group, which is characteristic of local anesthetics, precludes the ability to diffuse across the blood-brain barrier. 

Alkalosis Alkalosis shifts the equilibrium between NH4 and NH3 to the non-ionized, toxic NHs- Only this form is able to pass the blood-brain barrier and the membrane of the cerebral cells. (37) (s. fig. 15.2)... 

Antimuscarinics having a quaternary ammonium group are incompletely absorbed from the gut since these are completely ionized. The tertiary amine antimuscarinics are readily absorbed from the gut. The presence of food may reduce absorption. Quaternary ammonium antimuscarinics exhibit poor lipid solubility, do not cross the blood-brain barrier, and thus exhibit minimal central nervous system (CNS) effects. Also due to their poor lipid solubility they do not penetrate the eye and are unlikely to appear in the milk. Atropine and other tertiary amines are capable of crossing the CNS. Atropine is capable of crossing the placenta and has been stated to distribute into milk in small quantities. It is oxidized primarily in the liver. Atropine is apparently metabolized in the liver to tropic acid, tropine, and possibly esters of tropic acid and glucuronide conjugate. 

The existence of the blood-brain barrier does not preclude the passage of chemicals into the brain. As is the case with all other cellular membranes in the body, lipid-soluble nonionized chemicals enter the brain by passive diffusion. Anesthetics, ethanol, and CNS depressants, for instance, rapidly diffuse into the brain in a matter of a few seconds or minutes. They also exit the brain rapidly when the concentration gradient between blood and brain is reversed. Elemental mercury, methylmercury, and tetraethyl lead are examples of lipid-soluble forms of metals that easily enter the brain, while the ionized, much less lipid-soluble inorganic salts of mercury and lead penetrate only poorly. 

Rg = H or CH, Rg = Et, R4 = Ph), which have pifa in the range of 7-8 and are 40-60% dissociated, are capable of crossing the blood-brain barrier and exertingCNS effeets, including sedation. It was shown that the ionized form of barbiturates can permeate liposomal bilayers provided that 5-substituents impart sufficient lipophilicity (157). 

Because protein-bound drug cannot diffuse through the dialysis probes, the concentrations of I and II in the brain and plasma are representative of the free drug. Figure 6 is a plot of the plasma and brain extracellular fluid concentrations of I and II on the same time scale. The parent compound is able to cross the blood—brain barrier much more efficiently than the metabolite. The lower limit of quantitation (LLQ) for each compound in brain dialysate and plasma were 500 pg/mb and 1 ng/mb, respectively. Other applications of atmospheric pressure ionization MS have been reported for drugs in dialysate [14,15]. In one recent study, atmospheric pressure chemical ionization (APCI) LC/MS resulted in attomole detection limits with a linear response over 4 decades for anandamide, an endogenous cannabinoid. 

Thermospray ionization has also been used with quadrupole mass spectrometry to investigate the novel anticonvulsant topiramate in rat brain [16]. Topi-ramate crosses the blood—brain barrier and the concentration of the drug remains in the micromolar range for more than 6 hr. Samples were collected every 15 min over this time period, and the authors planned to analyze the dialysate without further sample cleanup. Distilled water was used as the perfusion medium to minimize the effect of dialysis salts on the mass spectrometer. I lowcver, it is important to note that microdialysis is best performed with matching ionic... 

The determinants of blood-brain barrier penetration are similar to the determinants of membrane permeability. They include lipophilicity (log P), H-bonding capacity, ionization prohle, size, and flexibility. An example of a simple quantitative structure-activity relationship (QSAR) equation to calculate the ratio of the steady state concentration of the drug molecule in the brain and in the blood have been described" (for a comprehensive review of the in silico methods see" ) ... 

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