Does anyone know of recordings of 2D MDCK / BMEC permeability or 3D rat brain perfusion measurements of temozolomide permeability?
Thanks!
My recollection of our data is that TMZ was aqueous boundary layer-limited, or it's apparent permeability coefficient would be dependent upon how well the model system used to measure it is mixed. In our MDR1-MDCK cell monolayer assay, TMZ had a Papp of ~65 x 10^-6 cm/sec. In vivo, TMZ is rapidly metabolized in blood so we couldn't get a good measure of its BBB permeability; however, brain-to-plasma ratios of TMZ were very high within 5 min of an IV (tail vein) dose. In other words, TMZ equilibrated across the BBB rapidly and once in the brain was protected from rapid degradation whereas the blood-borne TMZ was very low due to degradation. We never measured the metabolic product. Unfortunately, since I am retired I no longer have access to such data.
Hello Dr. Raub, thank you so much for your assistance. Would you be able to guide me towards a specific publication in which the 65x10^-6 cm/sec value was calculated for MDCKs? Thanks!
I'm really unsure if the value's been published. If mentioned, it might be in Drug Metab. Dispos. 43(9):1360-1371. The method is there.
Tsinman et al 2011, Avdeef & Sun 2011 developed a BBB prediction model, based on ~600 in situ brain perfusion values (list in Absorption and Drug Development, 2012) , according to which the predicted BBB Papp = 1.86 x 10-6 cm/s. If one can assume that temozolomide is not a substrate to a transporter, then the permeability is predicted to be 1% flow limited, 18% via paracellular, with the remainder via transcellular passive route.
Thank you Dr. Avdeef, Dr. Raub
In extension to the question about temozolomide:
I'm wondering if anyone is sitting in with a Blood-Brain Barrier permeability value (2D MDCK cell value or a 3D brain perfusion value) for aripiprazole or methylphenidate(ritalin)?
Hi Christian,
There are nearly 600 in situ BBB permeability entries in Table 9.7 in Absorption and Drug Development (2012). Unfortunately, the 3 molecules you mention are not there. However, Caco-2/MDCK rhodamine 123 values may be found in: (1) Kanaan M, et al. Curr. Drug Metab. 2008, 9, 144-151; (2) Troutman MD, Thakker DR. Rhodamine 123 requires carrier-mediated influx for its activity as P-glycoprotein substrate in Caco-2 cells. Pharm. Res. 2003, 20, 1192-1199; (3) Wang Q, et al. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int. J. Pharm. 2005, 288, 349-359. Transporter effects are complicated.
Best,
Alex
Thank you Dr. Avdeef,
I am also working with Nicotine, and Abilify (aripiprazole), would you happen to know if there are measured values for any of these? Again, so far extensive searches of Pubmed have revealed nothing.
Hi Christian,
I have not seen in situ brain perfusion (PS) values for either nicotine or aripiprazole. Tom Raub published nicotine Caco-2 & MDCK values for nicotine: 178-399 x10-6 cm/s (intrinsic values): Garberg P, et al. In vitro models for the blood-brain barrrier.Toxicol. In Vitro 2005, 19, 299-334. I've attached pCEL-X predictions: aripiprazole PS = 278 x 10-4 mL/s/g, nicotine PS = 73 x 10-4 mL/s/g. Hope this helps. Maybe Tom can add more.
Alex
Hello Dr. Avdeef,
I was wondering if you could help us with the value for ritalin (methylphenidate)?
Hi Christian,
I don't have measured values for the permeability of Ritalin in my databases. The pKa was reported as pKa 8.80 in Siegel et al. J. Am. Pharm. Assoc. 48(1959) 431-439. The pCEL-X predicted values are in the attached pdf file. Hope this helps.
Cheers,
Alex
Thank you very much for the help with Nicotine and Ritalin,
Kind regards
Dear Dr. Avdeef, I was wondering if I could pick your brain again. I'm still looking for a BBB brain perfusion value for nicotine. I have the following paper https://jpet.aspetjournals.org/content/jpet/314/2/636.full.pdf with a brain perfusion model for nicotine. However all values are given as permeability-surface area products (PA). Is there a way of transferring this value to a 3D brain perfusion permeability P?
Hi Christian,
It's usually reasonable to assume there are 100 cm2 per gram of rodent brain tissue. If the PA values are in units of 10-4 mL/g.s, then simply divide the PA value by 100 to get P in units of 10-6 cm/s.
(I don't have access to Paul Lockman's article. Maybe you can get his take on the unit conversions, if I understood correctly.)
Cheers,
Alex
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