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

Abstract

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.

Metabolism and Disposition of Imatinib Mesylate in Healthy Volunteers

“…With CL/f of 4.18 (ml/min)/kg (18.9 Ϯ 2.0 l/h) and f ϳ 1, the plasma clearance of imatinib was approximately 4.2 (ml/min)/kg. From this value and a fraction in plasma of 74% at a hematocrit of 46% (Kretz et al, 2004), a moderate blood clearance of 5.8 (ml/min)/kg corresponding to 28% of the hepatic blood flow in humans [21 (ml/min)/kg; Davies and Morris, 1993] can be calculated. The apparent volume of distribution V z /f of imatinib found in the present study (366 Ϯ 19 liters, mean Ϯ S.D.)…”

“…Systemic exposure to imatinib and its metabolites in plasma (P) is expressed as AUC 0 -24 h in mol⅐h/l, and percentage of total ͓ 14 C͔AUC 0 -24 h is given within parentheses. Radiolabeled components detected in urine and feces are indicated as U and F. Amounts of imatinib and its metabolites in urine (0 -72 h) and feces (0 -168 h) (Kretz et al, 2004). Excretion and Mass Balance in Urine and Feces.…”

“…Factor f means the systemic bioavailability of the drug. The systemic clearance in blood was calculated by CL Blood ϭ CL Plasma ϫ F plasma /(1 Ϫ HCT), where HCT indicates the hematocrit value, and F Plasma ϭ (C Plasma /C Blood ) ϫ (1 Ϫ HCT) means the fraction of imatinib in the plasma compartment obtained from an in vitro blood distribution study in human volunteers (Kretz et al, 2004).…”

A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response

“…28,29 We therefore determined the IC 50 values of KW-2449 and M1 for FLT3 and STAT5 using Molm14 cells, substituting normal human plasma for culture medium. In plasma, the IC 50 for P-FLT3 inhibition shifts approximately 10-fold to 144 nM for KW-2449 (Figure 2A,B).…”

Pharmacokinetic Investigation of Imatinib Using Accelerator Mass Spectrometry in Patients with Chronic Myeloid Leukemia

“…The development of resistance during chronic therapy is possibly linked to induction of a 1 -acid glycoprotein (6) or to changes in imatinib pharmacokinetics over time (30). With regard to binding to a 1 -acid glycoprotein, it is possible that imatinib and CGP74588 compete for binding sites, such that the fraction unbound in plasma will be affected both by changing concentrations of a 1 -acid glycoprotein in plasma and by changes in the relative concentrations of drug and metabolite (31). In the patients studied here, levels of a 1 -acid glycoprotein were not markedly elevated, with little variation among patients.…”