McGuire B W, Sia L L, Haynes J D, Kisicki J C, Gutierrez M L, Stokstad E L
Clinical Research Department, Alpha Therapeutic Corporation, Los Angeles, CA.
NCI Monogr. 1987(5):47-56.
Oral dose proportionality and pharmacokinetics of leucovorin [(d,l)-5-formyltetrahydrofolate (5-formyl-THF)] were studied in 30 healthy male subjects. In a randomized cross-over design, 24 fasted subjects were given 4 of a series of 5 single test doses between 20 and 100 mg, at 1-week intervals, of 5-formyl-THF as an oral solution of leucovorin calcium. Six separate subjects received 200 mg iv and po in a 2-way crossover. Blood and urine samples were collected over 24 hours for differential microbiological folate assays using Lactobacillus casei and Streptococcus faecalis. Using L casei activity to measure total serum folates, the area under the concentration-time curve from 0 to infinite time (AUC[0-infinity]) was calculated. Relative bioavailabilities were 78%, 62%, 49%, and 42% for the 40-, 60-, 80-, and 100-mg doses, respectively. Both the AUC and peak concentration (CPEAK) of total folates (consisting predominantly of the major metabolite, 5-methyltetrahydrofolate (5-methyl-THF], displayed significant deviation from linearity consistent with a saturation of folate absorption. Absolute bioavailability of the 200-mg oral dose of leucovorin based on AUC was 31% compared with that of the iv dose (6,848 vs. 22,298 ng.hr/ml, respectively). Total clearance, terminal half-life, and apparent volume of distribution of total folate at the 200-mg dose were not significantly different between the two routes of administration. Eighty-three percent of the biologically active iv dose was recovered in the urine within 24 hours, 31% as 5-methyl-THF. Twenty percent of the same oral dose was excreted in 24 hours, 16% as 5-methyl-THF. In contrast to the nondose-proportionality observed in total serum folates, AUC of the small component of S faecalis activity, which appeared earlier than 5-methyl-THF, displayed linear kinetics, suggestive of a distinct mechanism of uptake. As dose increased, S faecalis activity increased in relative proportion to L casei, indicating that saturation of the enzymatic bioconversion to 5-methyl-THF may also be occurring. In light of the demonstrated nondose-proportionality of total folates with oral leucovorin in this dose range, consideration should be given to parenteral administration in regimens employing higher doses. Oral administration should be at a level consistent with the capacity for efficient folate uptake.
在30名健康男性受试者中研究了亚叶酸钙[（d，l）-5-甲酰基四氢叶酸（5-甲酰基-THF）]的口服剂量比例和药代动力学。采用随机交叉设计，24名禁食受试者以1周的间隔，接受了一系列5个单剂量（20至100mg）中的4个剂量的5-甲酰基-THF，以亚叶酸钙口服溶液的形式给药。6名单独的受试者以双向交叉方式接受了200mg静脉注射和口服给药。在24小时内采集血液和尿液样本，使用干酪乳杆菌和粪肠球菌进行微生物学叶酸差异分析。使用干酪乳杆菌活性来测量总血清叶酸，计算从0至无限时间的浓度-时间曲线下面积（AUC[0-∞]）。40mg、60mg、80mg和100mg剂量的相对生物利用度分别为78%、62%、49%和42%。总叶酸（主要由主要代谢物5-甲基四氢叶酸（5-甲基-THF）组成）的AUC和峰浓度（CPEAK）均显示出与叶酸吸收饱和一致的显著线性偏差。基于AUC，200mg口服剂量亚叶酸钙的绝对生物利用度与静脉注射剂量相比为31%（分别为6,848和22,298 ng·hr/ml）。200mg剂量下总叶酸的总清除率、末端半衰期和表观分布容积在两种给药途径之间无显著差异。83%的生物活性静脉注射剂量在24小时内从尿液中回收，其中31%为5-甲基-THF。相同口服剂量的20%在24小时内排泄，其中16%为5-甲基-THF。与总血清叶酸中观察到的非剂量比例不同，粪肠球菌活性小部分的AUC显示出线性动力学，其出现早于5-甲基-THF，提示存在独特的摄取机制。随着剂量增加，粪肠球菌活性相对于干酪乳杆菌活性以相对比例增加，表明向5-甲基-THF的酶促生物转化也可能发生饱和。鉴于在此剂量范围内已证明口服亚叶酸钙时总叶酸的非剂量比例，在采用更高剂量的方案中应考虑胃肠外给药。口服给药应处于与有效叶酸摄取能力一致的水平。
