Author: Lee, Minchang ; Han, Hwa Seung ; Park, Jae Hyung ; Lee, Hansang ; Kang, Young Mo ; Jung, Dae-Woong ; Khatoon, Shakera ; Ikram, M ; Thambi, Thavasyappan ; Yi, Gi-Ra

To enhance cellular uptake and site-specific drug release in the tumor microenvironment, zwitterionic mesoporous silica nanoparticles (Z-MSN) were prepared by introducing a bioresponsive gatekeeper composed of negatively charged carboxylic groups and positively charged quaternary amine groups. When these Z-MSN encountered a mildly acidic environment, their surface charge readily switched from negative to positive by cleavage of an acid-labile maleic amide linkage, thus allowing for effective cellular uptake into tumor tissue. Doxorubicin (DOX) encapsulated in Z-MSN was not significantly released in physiological conditions (pH 7.4), whereas the release rate of DOX remarkably increased in mildly acidic conditions through disintegration of the gatekeeper. The antitumor efficacy of DOX-loaded Z-MSN (DOX-Z-MSN) was evaluated after their systemic administration to tumor-bearing mice. Compared to free DOX and DOX-loaded MSN without the gatekeeper, DOX-Z-MSN exhibited much higher antitumor efficacy in vivo. Overall, these results demonstrated that the hydrophilic negative surface of Z-MSN, with their closed gate, allowed for their effective accumulation in tumor tissue after systemic administration, and that their charge-swapping and gate-opening in the tumor environment enhanced their cellular uptake and drug release rate simultaneously, implying a highly promising potential for development of Z-MSN as a drug carrier for cancer therapy.STATEMENT OF SIGNIFICANCEIn an attempt to address the issues of enhanced cellular uptake and site-specific drug release of nanoparticles, we herein report on zwitterionic MSN (Z-MSN) with a pH-responsive gatekeeper which can be internalized into cancer cells via switching their surface charge from negative, in physiological conditions, to positive, in the tumor microenvironment. We hypothesized that the hydrophilic negative surface of Z-MSN with a closed gate allows for their accumulation into tumor tissue after systemic administration, whereas their charge-swapping and gate-opening in the tumor environment enhance cellular uptake and drug release rate simultaneously. Overall, Z-MSN constitute a promising drug delivery carrier for cancer therapy.

01 Aug 2005·Pharmacogenetics and GenomicsQ4 · MEDICINE

Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets

Q4 · MEDICINE

Article

Author: Brockmoeller, Juergen ; Henckel, Hanns-Benjamin ; Roots, Ivar ; Tzvetkov, Mladen ; Uebelhack, Ralf ; Kirchheiner, Julia ; Franke, Leonora ; Meineke, Ingolf

INTRODUCTIONCYP2D6 gene duplication causing ultrafast metabolism is one reason for failure in responding to CYP2D6-metabolized antidepressants. We studied the effect of the CYP2D6 duplication genotype on doxepin pharmacokinetics and platelet serotonin uptake and concentrations.METHODSPharmacokinetics of trans (E)- and cis (Z)-doxepin and N-desmethyldoxepin were analyzed after a single dose of 75 mg doxepin in 11 ultrafast metabolizers (UM), 11 extensive metabolizers (EM) and 3 poor metabolizers (PM), identified by genotyping for CYP2D6 alleles *2, *3, *4, *5, *6, *9, *10, *35, *41 and specific analyses to characterize gene duplication. Platelet serotonin concentrations were measured by HPLC.RESULTSA trend for lower AUC of the active principle (sum of doxepin and N-desmethyldoxepin) in UMs versus EMs was detected (575 versus 1,000 nmol h/l, P=0.07), mainly due to the differences in desmethyldoxepin concentrations (P=0.003). Stereoselective analysis showed a significant effect of the UM genotype on (E)-doxepin pharmacokinetic parameters whereas those of (Z)-doxepin did not differ between the CYP2D6 genotype groups. The 75-mg doxepin dose had no effect on platelet serotonin concentration and uptake, but serotonin concentrations in platelets were significantly higher in UM in comparison to the EM and PM groups. At baseline, these concentrations were 462, 399, and 292 ng/10 platelets in UM, EM and PM (P<0.0001 for trend).CONCLUSIONSAt the same dose, internal exposure to doxepin differed by more than ten-fold between the CYP2D6 genotype groups. CYP2D6 may have an effect on platelet serotonin explained by salvage pathways of 5-methoxytryptamine to serotonin mediated by CYP2D6; however, this finding requires further confirmatory experiments.

01 Oct 2002·Pharmacogenetics

Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers.

Article

Author: Brockmoeller, Juergen ; Mueller, Gunnar ; Roots, Ivar ; Meineke, Ingolf ; Kirchheiner, Julia

In-vitro data indicated a contribution of cytochrome P450 enzymes 1A2, 3A4, 2C9, 2C19 and 2D6 to biotransformation of doxepin. We studied the effects of genetic polymorphisms in CYP2D6, CYP2C9 and CYP2C19 on E- and Z-doxepin pharmacokinetics in humans. Doxepin kinetics was studied after a single oral dose of 75 mg in healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/*3. E-, Z-doxepin and -desmethyldoxepin were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics and by population pharmacokinetic modeling considering effects of genotype on clearance and bioavailability. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271), and 127 (124-139) l h(-1) in EMs, IMs and PMs of CYP2D6. In addition, EMs had about 2-fold lower bioavailability compared with PMs indicating significant contribution of CYP2D6 to E-doxepin first-pass metabolism. E-doxepin oral clearance was also significantly lower in carriers of CYP2C9*3/*3 (238 l h(-1) ). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l h(-1) in CYP2C19 PMs compared with 191 l h(-1) in EMs). The area under the curve (0-48 h) of the active metabolite -desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35, and 1.28 nmol l h(-1) in PMs, IMs, and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The CYP2D6 polymorphism had a major impact on E-doxepin pharmacokinetics and CYP2D6 PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses.

100 Deals associated with Cidoxepin

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KEGG	Wiki	ATC	Drug Bank
D03491	Cidoxepin	-	DB14750

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