The accumulation of mercaptopurine metabolites in age fractionated red blood cells.

Rostami‐Hodjegan, Amin; Lennard, Lynne; Lilleyman, J S

doi:10.1111/j.1365-2125.1995.tb05776.x

Cited by 21 publications

(11 citation statements)

References 22 publications

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“…The shifts of TPMT activities observed in leukaemic children may, in part, be due to the RBC age distribution of the study population. Methylmercaptopurine nucleotide concentrations (products of the TPMT reaction) do not differ between young and old RBCs and this observation has been taken to suggest that TPMT activities do not vary with RBC age [17]. This is in direct contrast with the studies reported in this paper and indicates the complexity of the biochemical background behind the formation of RBC thiopurine metabolites.…”

Section: Discussioncontrasting

confidence: 77%

“…Thiopurines are highly metabolized drugs and the liver plays a major role in the ultimate appearance of thiopurine metabolites within the RBC [13,15,25]. This could explain why the accumulation pro®le of 6MP metabolites is the same in all ages of RBCs [17], the function of the RBC may be to form nucleotides from thiopurine metabolites originating elsewhere. In vivo a major function of the RBC is the formation of nucleotides from endogenous purines [17,25].…”

Section: Discussionmentioning

confidence: 99%

“…This could explain why the accumulation pro®le of 6MP metabolites is the same in all ages of RBCs [17], the function of the RBC may be to form nucleotides from thiopurine metabolites originating elsewhere. In vivo a major function of the RBC is the formation of nucleotides from endogenous purines [17,25].…”

Section: Discussionmentioning

confidence: 99%

“…Firstly, a group of healthy adult volunteers and secondly, children with ALL when excess (5 ml) blood samples were provided for the measurement of TPMT at disease diagnosis. This technique has been described in detail elsewhere [17]. Brie¯y, leucocytes are removed from whole blood (4 ml) by ®ltering through cellulose and the eluted RBCs were washed and resuspended in saline to a haematocrit of 40%.…”

Section: Blood Fractionationmentioning

confidence: 99%

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Human thiopurine methyltransferase activity varies with red blood cell age

Lennard

Chew

Lilleyman

2001

Brit J Clinical Pharma

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Aims Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC. Methods Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age‐fractionated on Percoll density gradients. Results Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654–18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age‐fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5–12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035. Conclusions Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Blood Fractionationmentioning

confidence: 99%

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Human thiopurine methyltransferase activity varies with red blood cell age

Lennard

Chew

Lilleyman

2001

Brit J Clinical Pharma

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“…In our study, the impact of HDMTX on 6-MP intracellular disposition was assessed in erythrocytes after a minimum of 8 days of continuous daily 6-MP, and thus at steady state concentration [20]. Our data consolidate and provide a valuable complement of the previous unexpected Wnding that HDMTX can negatively impact the intracellular metabolism of 6-MP.…”

supporting

confidence: 61%