Monday, November 9, 2015

parkinson's: baicalein bioavailability, not good

The following does not address "oxidized" baicalein which was the most potent at dis-aggregating a-Syn.  I do not know if the oxidized form (a quinone) is "bioavailable" to the brain.

My summary:  very effective as B against a-Syn and easily crosses BBB, but it seems to be absorbed only 15% and is immediately converted to BG for transport to the liver.  No info on BG effect on a-Syn.  Definitely a possibility if BG works on a-Syn, but it is double the m.w. of B.

Baicalin (m.w. 446) (aka BG aka baicalein 7-O-glucuronide) is the primary metabolite of Baicalein (m.w. 270), but there is no research on its health effects.   But it appears to be absorbed less than Baicalein.

Baicalein was shown in 2004 to have an incredible ability to revert a-Syn aggregations, especially in its oxidized form.

peperine, curcumin, and (-)-epicatechin (a catechin isomer) increase bioavailability (absorption) and P and C prevent glucuronation of baicalein. Catechins are in teas, grapes, apples, lentils, and black-eyed peas

easily penetrated blood brain barrier in rats, especially if it was not allowed to undergo metabolism by P-glycoprotein which was inhibited by cyclosporin A (an immunosuppressant for transplants) which doubled concentration in brain.  Without cycloA, 60 mg/kg injected resulted in 1.5 ng/ml (5 nM) at 30 min and about half as much at 60 minutes (rapid elimination) and half as much if 30 mg/kg.  Was 3 times higher in blood verses brain tissue.

Monkeys given 50 to 500 mg/kg got 13 to 26% of it into blood.  ('bioavailable" means percent of oral compared to I.V.)

"glycosylation (not glucuronation) increased the bioavailability of baicalein by helping to protect this vital molecule from chemical or enzymatic oxidation." [keep in mind the oxidized form is more effective]

traditional concoction with "x grams of baicalein" had same bioavailability as concentrated powder of "x grams", FULL TEXT

Sulfation and P450 mediated hydroxylation of B were much less significant than glucuronidation (UDP-glucuronosyltranferase (UGT) in the extensive liver and intestinal first-pass glucuronidation )Three metabolites of B namely  baicalein 7-O-glucuronide (BG) [the main one], the isomer of baicalein 7-O-glucuronide (BG'), and baicalein sulfate were found.

soya lecithin best for nanoparticle delivery for myricetin, 3x higher

LCN increases B 4x in mice

doubling the dose from 2.5 to 5 mg/kg (injection) saturared rat ability to make conjugated forms, resulting in 8 uM after 3 minutes instead of 1.5 uM.  Initial concentration was about 70 uM, so pure form drops RAPIDLY.  See figure 4. The conjugated forms go just as quickly to the bile.  10 uM appears by my calculation to be 10% of dose assuming 270 m.w., 500 g rats with 50 ml blood.

baicalein may block some CYP3A liver enzymes (like peperine)
Good overall view, seems to exaggerate lack of bioavailability (most of his references are cited above):

Baicalin belongs to Class IV of Biopharmaceutical Classification System (BCS) due to the extremely low hydrophilicity (solubility 0.052 mg/mL in water) and lipophilicity (Papp = 0.037×10−6 cm/s) []. Baicalein is highly permeable (Papp = 1.7×10−5 cm/s) but poorly water soluble, which is classified as a Class II compound according to BCS [,]. The poor solubility results in both baicalin and baicalein very low bioavailability []. Extensive studies have been conducted to explore the in vivo processes of these two drugs. The serum profiles and pharmacokinetics of orally administered baicalein and baicalin were compared. Baicalin was absorbed more slowly and had lower Cmax than baicalein []. There exists wide complicated biotransformation of baicalin and baicalein in vivo (Figure 2). As a natural glycoside, baicalin possesses more favorable aqueous solubility than baicalein. However, baicalin is difficult to be absorbed as its parent form due to the poor lipophilicity. When baicalin was orally administered, only a small portion was absorbed as its original form by the body, and most was hydrolyzed to baicalein by intestinal bacterial []. The recovered baicalein was then extensively subjected to Phase 2 metabolism, and glucuronides and/or sulfates of baicalein were exclusively presented in the plasma. Notably, the circulating baicalin is not the administered parent drug but one of the conjugated metabolites of baicalein after oral administration of baicalin. The circulating baicalin reenters the gastrointestinal tract via the biliary excretion mechanism []and undergoes enterohepatic circulation []. After oral administration of baicalein, it is subjected to the extensive first-pass metabolism in liver and small intestine [,], and therefore, glucuronides/sulfates of baicalein including baicalin are predominant in the plasma []. The biotransformation of baicalin and baicalein and the enterohepatic circulation of baicalin can keep a balance in the systemic levels. With the oral administration of baicalin and baicalein, dominantly circulating in the plasma are the glucuronides/sulfates of baicalein, and therefore, the conjugated metabolites are actually responsible for the in vivo effects. Because baicalin itself is one of the conjugated metabolites after oral administration of baicalin or baicalein, the activity of baicalin reported in in vitro studies can only partially explain the in vivo effects of baicalin and baicalein [].

Figure 2

The potential biotransformation pathways of baicalin and baicalein in vivo
A sound knowledge of the pharmacokinetic characteristics of baicalin and baicalein enables scientists to further optimize use of these agents. Various formulations have been developed to improve the oral bioavailability of baicalin and baicalein. Baicalein nanocrystal [], baicalein-hydroxypropyl-β-cyclodextrin inclusion complex [], baicalein self-microemulsifying drug delivery system [], and baicalein solid dispersion []have been developed to improve dissolution and oral bioavailability of baicalein. Some nano-based formulations such as solid nanocrystals [], nanoemulsions [], and solid lipid nanoparticles []have been designed for increasing baicalin's solubility and absorption rate and improving its oral bioavailability. Besides, change administration route of baicalein may be employed to avoid the first-pass effect of the gastrointestinal tract or liver and enhance its bioavailability. For example, pulmonary administration of baicalein nanocrystal can obtain similar pharmacokinetic parameters to intravenous injection of baicalein solution [].

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