Library

X
feed icon rss

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Electronic Resource
    Electronic Resource
    Quantitative Prediction of In Vivo Drug-Drug Interactions from In Vitro Data Based on Physiological Pharmacokinetics: Use of Maximum Unbound Concentration of Inhibitor at the Inlet to the Liver (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 336-343 
    Details
    ISSN: 1573-904X
    Keywords: drug interaction ; prediction ; physiologically-based pharmacokinetics ; tolbutamide ; sulfaphenazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess the degree to which the maximum unboundconcentration of inhibitor at the inlet to the liver (Iinlet,u,max), used in theprediction of drug-drug interactions, overestimates the unboundconcentration in the liver. Methods. The estimated value of Iinlet,u,max was compared with theunbound concentrations in systemic blood, liver, and inlet to the liver,obtained in a simulation study based on a physiological flow model.As an example, a tolbutamide/sulfaphenazole interaction was predictedtaking the plasma concentration profile of the inhibitor intoconsideration. Results. The value of Iinlet,u,max differed from the concentration in eachcompartment, depending on the intrinsic metabolic clearance in theliver, first-order absorption rate constant, non-hepatia clearance andliver-to-blood concentration ratio (Kp) of the inhibitor. The AUC oftolbutamide was predicted to increase 4-fold when co-administeredwith sulfaphenazole, which agreed well with in vivo observations andwas comparable with the predictions based on a fixed value of Iinlet,u,max.The blood concentration of tolbutamide was predicted to increase whenit was co-administered with as little as 1/100 of the clinical doseof sulfaphenazole. Conclusions. Although Iinlet,u,max overestimated the unboundconcentration in the liver, the tolbutamide/sulfaphenazole interaction couldbe successfully predicted by using a fixed value of Iinlet,u,max, indicatingthat the unbound concentration of sulfaphenazole in the liver after itsclinical dose is by far larger than the concentration to inhibitCYP2C9-mediated metabolism and that care should be taken when it isco-administered with drugs that are substrates of CYP2C9.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007509324428
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4 (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 419-426 
    Details
    ISSN: 1573-904X
    Keywords: drug interaction ; mechanism-based inhibition ; triazolam ; erythromycin ; physiologically-based pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantitatively predict the in vivo interaction betweentriazolam and erythromycin, which involves mechanism-basedinhibition of CYP3A4, from in vitro studies using human liver microsomes(HLM) and recombinant human CYP3A4 (REC). Methods. HLM or REC was preincubated with erythromycin in thepresence of NADPH and then triazolam was added. α- and 4-hydroxy(OH) triazolam were quantified after a 3 min incubation and the kineticparameters for enzyme inactivation (kinact and K′ app) were obtained.Drug-drug interaction in vivo was predicted based on aphysiologically-based pharmacokinetic (PBPK) model, using triazolam anderythromycin pharmacokinetic parameters obtained from the literature and kineticparameters for the enzyme inactivation obtained in the in vitro studies. Results. Whichever enzyme was used, triazolam metabolism was notinhibited without preincubation, even if the erythromycin concentrationwas increased. The degree of inhibition depended on preincubationtime and erythromycin concentration. The values obtained for kinactand K′ app were 0.062 min−1 and 15.9 μM (α-OH, HLM), 0.055 min−1and 17.4 μM (4-OH, HLM), 0.173 min−1 and 19.1 μM (α-OH, REC),and 0.097 min−1 and 18.9 μM (4-OH, REC). Based on the kineticparameters obtained using HLM and REC, the AUCpo of triazolamwas predicted to increase 2.0- and 2.6-fold, respectively, followingoral administration of erythromycin (333 mg t.i.d. for 3 days), whichagreed well with the reported data. Conclusions. In vivo interaction between triazolam and erythromycinwas successfully predicted from in vitro data based on a PBPK modelinvolving a mechanism-based inhibition of CYP3A4.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007572803027
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Effects of Intestinal CYP3A4 and P-Glycoprotein on Oral Drug Absorption—Theoretical Approach (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 225-231 
    Details
    ISSN: 1573-904X
    Keywords: oral absorption ; CYP3A4 ; P-glycoprotein ; diffusion model ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the effects of gut metabolism and efflux on drug absorption by simulation studies using a pharmacokinetic model involving diffusion in epithelial cells. Methods. A pharmacokinetic model for drug absorption was constructed including metabolism by CYP3A4 inside the epithelial cells, P-gp-mediated efflux into the lumen, intracellular diffusion from the luminal side to the basal side, and subsequent permeation through the basal membrane. Partial differential equations were solved to yield an equation for the fraction absorbed from gut to the blood. Effects of inhibition of CYP3A4 and/or P-gp on the fraction absorbed were simulated for a hypothetical substrate for both CYP3A4 and P-gp. Results. The fraction absorbed after oral administration was shown to increase following inhibition of P-gp. This increase was more marked when the efflux clearance of the drug was greater than the sum of the metabolic and absorption clearances and when the intracellular diffusion constant was small. Furthermore, it was demonstrated that the fraction absorbed was synergistically elevated by simultaneous inhibition of both CYP3A4 and P-gp. Conclusions. The analysis using our present diffusion model is expected to allow the prediction of in vivo intestinal drug absorption and related drug interactions from in vitro studies using human intestinal microsomes, gut epithelial cells, CYP3A4-expressed Caco-2 cells, etc.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018872207437
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...