Distribution of 7-hydroxymethotrexate in human blood

Slørdal, Lars; Sager, Georg; Huseby, Nils‐Erik; Aarbakke, Jarle

doi:10.1111/j.2042-7158.1988.tb05149.x

Cited by 7 publications

(1 citation statement)

References 16 publications

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“…The hydroxylated metabolite is less water soluble than the parent compound [2]. Also, the protein binding of 7-OH-MTX is higher than that of MTX [22].…”

Section: Discussionmentioning

confidence: 99%

Plasma and urine levels of methotrexate and 7‐hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate

Skoglund

Söderhäll²,

Beck³

et al. 1994

Med. Pediatr. Oncol.

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A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.

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“…The hydroxylated metabolite is less water soluble than the parent compound [2]. Also, the protein binding of 7-OH-MTX is higher than that of MTX [22].…”

Section: Discussionmentioning

confidence: 99%

Plasma and urine levels of methotrexate and 7‐hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate

Skoglund

Söderhäll²,

Beck³

et al. 1994

Med. Pediatr. Oncol.

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Prediction of human blood‐to‐plasma drug concentration ratio

Uchimura¹,

Kato²,

Saito³

et al. 2010

Biopharm & Drug Disp

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The objective of this study was to predict R(b) (blood/plasma ratio) in humans using a simple method. Human and rat R(b) and free fraction in plasma (f(p)) values were obtained from the literature. The ratio of total red blood cell concentration to the free concentration in plasma (K(b)) was calculated using f(p) and R(b). Four methods were used for the prediction of R(b): (A) use of rat R(b); (B) use of R(b) calculated from rat K(b) and human f(p); (C) correlation of human log ((1-f(p))/f(p)) and human log K(b); and (D) correlation of log D with human log K(b). The R(b) of 96 compounds in humans ranged from 0.52 to 2.00, with an average of 0.89. A significant correlation was observed among human log K(b), human log ((1-f(p))/f(p)), and log D; however, no obvious correlation was observed among human R(b), human log ((1-f(p))/f(p)), and log D. The errors within 1.25-fold for methods A-D were 68.3%, 77.6%, 61.5% and 64.8%, respectively. All predictive methods considered here were superior to the use of the average value of human R(b) or R(b)=1. Rat R(b) corrected by human f(p) improved the accuracy of the prediction. Method B was the most accurate of the four methods.

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