Clinical pharmacokinetics of methotrexate in children.
Among the few antineoplastic agents investigated pharmacologically in children and adults, methotrexate has been clearly demonstrated to be handled differently in the two age groups. Age has in fact proved to be a major determinant, exerting an effect on both the pharmacokinetics and pharmacodynamics of methotrexate. Its pharmacokinetics, in turn, determine the drug toxicity. The beta-phase of methotrexate clearance, represented by the plasma drug concentration 48 hours from the start of a 6-hour infusion in a high dose treatment regimen, appears to be constant with age. In children, an increasing plasma drug concentration is apparent with increasing age, but whether this trend reflects a potential increase in the area under the plasma concentration-time curve of methotrexate has yet to be defined. Recent investigations have suggested that the drug is more completely distributed in the tissues of children than adults at the same infused dosage. This may explain the increased tissue toxicity caused by methotrexate. However, other observations suggest a faster drug turnover rate in the tissues of children. This may prevent the drug from concentrating in vital organs. Whether the metabolism of methotrexate, particularly the biosynthesis of methotrexate polyglutamates, plays a role in the biological effect of the drug is worthy of further investigation. The high brain tissue concentration after systemic methotrexate infusion and the slower efflux of methotrexate from brain tissues and cerebrospinal fluid make these tissues vulnerable to methotrexate toxicity.
D000293:Adolescent; D000375:Aging; D000970:Antineoplastic Agents / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005502:Food; D006801:Humans; D007263:Infusions, Parenteral; D007700:Kinetics; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism
D000970:Antineoplastic Agents; D008727:Methotrexate