Distribution of 7-hydroxymethotrexate in human blood.
We have examined the in-vitro distribution of 7-hydroxymethotrexate (7-OH-MTX), a cytotoxic metabolite of methotrexate (MTX), in human blood, and its protein binding in serum. The distribution of 7-OH-MTX (10(-6) M) in fresh samples of whole blood was studied at 37 degrees C and pH 7.51 +/- 0.05 (mean +/- s.d.), and its protein binding was assessed by equilibrium dialysis of serum against Krebs Ringer phosphate buffer at 37 degrees C and pH 7.41 +/- 0.07 (mean +/- s.d.). 7-OH-MTX had a mean cell/plasma concentration ratio of 0.03 (range 0-0.27, n = 18). It was extensively bound in human serum, with a bound fraction of 90.4 +/- 3.3% (mean +/- s.d.) in healthy volunteers (n = 11), and significantly lower, 82.3 +/- 4.0% (mean +/- s.d.), in hypoalbuminaemic surgical patients (n = 7). The binding of 7-OH-MTX was correlated with serum albumin (HSA) concentrations (r = 0.72, P less than 0.0007, n = 18). Blood distribution data support the contention that 7-OH-MTX has a small volume of distribution, and HSA appears to be mainly responsible for the high degree of its protein binding in serum.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000097:blood; D005493:Folic Acid Antagonists / Q000097:blood*; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood; D008875:Middle Aged; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism
D001798:Blood Proteins; D005493:Folic Acid Antagonists; D008055:Lipids; D012709:Serum Albumin; D005492:Folic Acid; C011864:7-hydroxymethotrexate; D008727:Methotrexate