Differences between in Vivo and in Vitro Sensitivity to Imatinib of Bcr/Abl+ Cells Obtained from Leukemic Patients

Gambacorti‐Passerini, Carlo; Rossi, Francesca; Verga, Magda; Ruchatz, Holger; Gunby, Rosalind H.; Frapolli, Roberta; Zucchetti, Massimo; Scapozza, Léonardo; Bungaro, Silvia; Tornaghi, Lucia; Rossi, Fábio; Pioltelli, Pietro; Pogliani, Enrico Maria; D’Incalci, Maurizio; Corneo, Gianmarco

doi:10.1006/bcmd.2002.0526

Cited by 34 publications

(26 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For imatinib elevated levels of AGP have been related to in vivo resistance in mouse [9] and humans [14,15], whereas other investigators did not observe any relevant binding of imatinib to AGP employing fluorescence quenching [16]. The data presented here, based on direct measurement of drug concentrations with radiolabelled compounds, confirmed high binding to AGP.…”

Section: Discussionsupporting

confidence: 49%

In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia

Kretz¹,

Weiss²,

Schumacher³

et al. 2004

Brit J Clinical Pharma

View full text Add to dashboard Cite

AimsTo determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non‐human species.MethodsThe blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using 14C labelled compounds.ResultsThe mean fraction of imatinib in plasma (fp) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, fp for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AML patients (2.3–6.5% at concentrations ≤ 5000 ng ml−1) compared to monkey and dog (7.6–19%). Both compounds displayed high binding to human α1‐acid glycoprotein. AML patients had a reduced haematocrit and showed greatest variability in their blood binding parameters.ConclusionImatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.

show abstract

Section: Discussionsupporting

confidence: 49%

In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia

Kretz¹,

Weiss²,

Schumacher³

et al. 2004

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…21 Moreover, AGP levels in humans are 4-5 times higher than in mice, so fundamental PK properties of imatinib such as binding to plasma proteins differ significantly between rodents and man. 11,22 Also, while imatinib does not appear to be a human PXR activator, it has not been screened against other receptors that can sense xenobiotic compounds such as CAR, which exhibits substantial cross species differences in its activation profile.…”

Section: Commentarymentioning

confidence: 99%

“…Imatinib is 95% bound to plasma proteins, mainly albumin and alpha 1 acid glycoprotein (AGP). 11 Pharmacokinetic data in healthy volunteers and patients with CML and GIST shows an average terminal elimination half-life of 18 hours and excellent absorption with bioavailability of 98%, so it is unlikely that downregulation or inhibition of absorption is a major contributor to drug resistance. Only about 10% of imatinib is renally cleared, with hepatic metabolism and biliary excretion being the main routes of elimination as demonstrated by the fact that over 80% of unchanged or metabolized imatinib can be recovered from feces.…”

mentioning

confidence: 99%

Transporter pumps and imatinib: A cause of pharmacokinetic resistance?

Klumpen

Liddle

2008

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…3,4 As a member of the lipocalin family, the single polypeptide chain of AAG folds into a β-barrel structure enclosing a wide, central cavity where a broad array of organic compounds can be bound. 5,6 Macrolide antibiotics are typical AAG binding agents [7][8][9] possessing a large macrocycle which is reminiscent to that of the potent immunosuppressive drug sirolimus (rapamycin). Sirolimus is a chiral, multichromophoric antifungal compound of bacterial origin consisting of triene, lactone, lactol, enone, and ketone moieties (Scheme 1).…”

mentioning

confidence: 99%

Orosomucoid binding induced amplification of inherent chirality of the immunosuppressant drug sirolimus

Zsila

2015

RSC Adv.

View full text Add to dashboard Cite

The circular dichroism (CD) activity of the lactone and enone groups are displayed below 250 nm. The asymmetrically perturbed n→π * transitions of the 9-, 26-, and 32-ones give rise to a negative CD band centered around 300 nm (Fig. 1). 12 The weak, π→π * of origin contribution of the triene moiety is suppressed by the more intense carbonyl Cotton effects (CEs) and can only be seen as unresolved vibrational peaks on the short-wavelength side of the n→π * feature. 12 The presence of the AAG in the sample solution, however, deeply alters this chiroptical profile amplifying the CD amplitudes in the absorption region of the triene chromophore (Fig. 1). The molar dichroic absorption coefficient (∆ε) measured in protein-free buffer solution at 275 nm increases by ten-fold and the anisotropy factor (g = ∆ε/ε) between 260-280 nm raises also by an order of magnitude (~10 -4 → ~10 -3 ). Concomitantly, the g max value of the n→π * CE is bathochromically shifted by 5 nm (Fig. 2). The excitation energy of n→π * transition of the carbonyl chromophore sensitively depends on the polarity of the medium. The binding of sirolimus to its the pharmacological target protein named FKBP is also accompanied with some modest CD and UV spectroscopic changes that refer to a more planar and rigid conformation of the triene moiety adopted at the binding site. 12It is to be noted that the related immunosuppressive drug tacrolimus lacks the triene component. Despite of its AAG association, 17 the intrinsic n→π * CE of tacrolimus shows no alteration in protein solution (Fig. S1, ESI) pointing out the importance of the triene chromophore in the CD spectroscopic detection of the binding interaction. properties. [20][21][22] Therefore, the interaction of sirolimus with the separated genetic variants of AAG has also been studied. The F1/S variant induced very similar CD changes and UV shift as seen with the native sample (Fig. 3). In marked contrast, the A form caused a much smaller intensity gain of the π→π * CE and only a minor red shift of the absorption maxima. Overall, it is shown for the first time that the conformational chirality of the triene chromophore allows the chiroptical sensing and evaluation of sirolimus-AAG interactions providing a basis to use this methodology for studying related compounds, too (e.g., temsirolimus, everolimus, ridaforolimus).

show abstract

Differences between in Vivo and in Vitro Sensitivity to Imatinib of Bcr/Abl+ Cells Obtained from Leukemic Patients

Cited by 34 publications

References 22 publications

In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia

In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia

Transporter pumps and imatinib: A cause of pharmacokinetic resistance?

Orosomucoid binding induced amplification of inherent chirality of the immunosuppressant drug sirolimus

Contact Info

Product

Resources

About