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PubMed2005

Homocysteine and folic acid: implications for pregnancy.

The role of folic acid and homocysteine in pregnancy is becoming clearer. The efforts of many countries to prevent neural tube defects through public awareness of folic acid have been disappointing, but evidence is now emerging that the food fortification programs in the United States and Canada are effective in reducing the numbers of neural tube defects, and there may be additional benefits in terms of other congenital defects such as oral-facial clefts and congenital heart disease. Homocysteine has a significant association with vascular disease in later life, is elevated in preeclampsia, and has been associated with other pregnancy complications such as early pregnancy loss. The data from cohorts of women with a history of preeclampsia during pregnancy indicate that they are at increased risk for cardiovascular and cerebrovascular disease in later life. Elevated homocysteine concentrations may be a common link that accounts for these associations.

Canada↗

PubMed2001

Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects.

CONTEXT: Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 microg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998. OBJECTIVE: To evaluate the impact of food fortification with folic acid on NTD birth prevalence. DESIGN, SETTING, AND POPULATION: National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999. MAIN OUTCOME MEASURE: Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999). RESULTS: The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care. CONCLUSIONS: A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

Folic Acid↗

PubMed1991

Folic acid absorption in patients infected with the human immunodeficiency virus.

To determine the folic acid absorption characteristics of patients with human immunodeficiency virus (HIV) infection, a prospective, controlled, result-blind single-dose oral absorption study was conducted. A total of 25 subjects were fasted and given 5 mg oral folic acid; blood samples were taken at time zero and after 30, 60, 90 and 180 min. Absorption of folic acid appears to be significantly impaired in HIV disease, irrespective of the stage of the disease and notwithstanding gastro-intestinal complaints, pathogen-negative diarrhoea or drug treatment. We here present functional data, complementary to previously reported structural and biochemical findings, to support the hypothesis that the virus can cause an enteropathy in the absence of opportunist infection. Folinic acid is absorbed by the same gut mechanism as folic acid, so caution may be needed when employing oral folinic acid rescue procedures in these patients, even when resting serum and red cell folate levels appear to be normal.

Absorption↗

PubMed1992

Relative bioavailability of deuterium-labeled monoglutamyl tetrahydrofolates and folic acid in human subjects.

The bioavailability of orally administered monoglutamyl folic acid and various (6S)-tetrahydrofolates was examined in humans with stable-isotope methods. Folic acid (PteGlu), tetrahydrofolate (H4folate), 5-formyl-H4folate, 10-formyl-H4folate, and 5-methyl-H4folate were prepared for oral administration in 3',5'-2H2 labeled (d2) form, and [glu-2H4]folic acid (d4-PteGlu) was prepared for intravenous injection. In each of five trials, fasting adult males (n = 7) on a folate saturation regimen (2 mg/d) were given a single oral dose of one of the d2-folates in apple juice, as well as an intravenous injection of d4-PteGlu as a control. Urine was collected for 48 h and the isotope labeling of urinary folates determined by mass spectrometry. Isotope excretion ratios of urinary folates were used as criteria of bioavailability (pooled SE = 0.10): PteGlu (1.53, least squares mean), 10-formyl-H4folate (1.02), 5-methyl-H4folate (0.99), 5-formyl-H4folate (0.1.13), and H4folate (0.71). These results indicate that differences exist in the bioavailability of monoglutamyl folates under these experimental conditions. This variation, whether due to differences in absorption or postabsorptive events, must be considered in quantitative studies of folate utilization with this type of protocol.

Administration, Oral↗

PubMed1995

Vitamin B12, folic acid, ferritin and haematological variables among Thai construction site workers in urban Bangkok.

Serum vitamin B12, folic acid, ferritin and haematological variables were investigated in eighty-seven male and nineteen female construction site workers in Bangkok. Haemoglobin concentration, haematocrit and MCHC were found to be higher in male than in female workers. Serum ferritin was slightly higher in males than in females. Serum B12 was found to be higher in male than in female workers and serum folic acid level were significantly higher in female than in male workers. Vitamin B12 deficiency was found in 2.3 per cent and folic acid deficiency in 6.9 per cent of the male workers. Serum vitamin B12 and folic acid levels were normal for female workers. The adequate serum levels of vitamin B12 and folic acid might be the result of the habit of the workers to consume tonic drinks which contain glucose, caffeine, and vitamins especially vitamins B6, and B12.

Adolescent↗

PubMedDate not supplied

Trends in periconceptional folic acid use by relatives in Irish families with neural tube defects.

Close relatives in families who have a child with a neural tube defect (NTD) are at greatly increased risk of having an affected child. Periconceptional folic acid reduces the risk of both occurrence and recurrence of NTDs substantially. Public health authorities currently recommend that the diets of all women between the ages of 15 and 44 who are capable of becoming pregnant be supplemented with folic acid tablets daily. We wondered if relatives in NTD families were more likely to use folic acid. From data obtained by interview with uncles and aunts in Irish NTD families we evaluated folic acid use in 144 of their pregnancies occurring between 1990 and 2000. There was a significant trend towards increasing use of folic acid both before and during pregnancy over the 10 years covered by the study. During the most recent years, 1998-2000, 57.9% of pregnancies reported by aunts were supplemented beforehand and 89.5% during the pregnancy. Pregnancies to smokers were significantly less likely to be supplemented with folic acid. In this study close relatives of an NTD child were more likely to report periconceptional folic acid use than the general public. While these results are encouraging, more remains to be done to ensure in this high risk group to ensure that the full prevention potential of folic acid is realised.

Dietary Supplements↗

PubMed1988

Effect of high levels of dietary folic acid on folate metabolism in vitamin B12 deficiency.

The effect of administering high levels of folic acid to vitamin B12-deficient animals was studied. In B12 deficiency histidine oxidation is decreased. This is the result of both decreased liver folate levels and increases in the proportion of methyltetrahydrofolates. The purpose of this study was to determine if the addition of very high levels of folic acid to B12-deficient diets could increase liver folates and thereby restore histidine oxidation. Rats were fed a soy protein B12-deficient diet containing 10% pectin which has been shown previously to accelerate B12 depletion. When this diet was supplemented with B12 and folic acid, histidine oxidation was 5.4% in 2 h and the livers contained 3.49 micrograms of folate/g. In the absence of B12, the histidine oxidation rate was 0.34% and the liver folate level was 1.33 micrograms/g. When 200 mg/kg of folic acid was added to the B12-deficient diet there was no increase in histidine oxidation (0.35%) but the liver folates were increased to 3.68 micrograms which is about the same as that with B12 supplementation. The percentage tetrahydrofolate of the total liver folates was the same with and without a high level of dietary folic acid. Thus there was an increase in the absolute level of tetrahydrofolate without any increase in folate function as measured by histidine oxidation. Red cell folate levels were the same with and without B12, which is in contrast to the markedly lower liver folate levels in B12 deficiency. These data suggest a difference between B12 regulation of folate metabolism in the liver and in the bone marrow.

Animals↗

PubMed2002

Optimization of folic acid, vitamin B(12), and vitamin B(6) supplements in pediatric patients with sickle cell disease.

Using homocysteine as a functional marker, we determined optimal folic acid, vitamin B(12), and vitamin B(6) dosages in 21 pediatric sickle cell disease (SCD) patients (11 HbSS, 10 HbSC; 7-16 years). Daily supplements of folic acid (400, 700, or 1,000 microg), vitamin B(12) (1, 3, or 5 U.S. 1989 RDA), and vitamin B(6) (1 or 3 U.S. 1989 RDA) were gradually increased in an 82-week dose-escalation study. Blood was taken at 9 occasions for measurements of erythrocyte (RBC) and serum folate, plasma vitamin B(12), whole-blood vitamin B(6), and plasma homocysteine. Augmentation of folic acid from 700 to 1,000 microg and vitamin B(12) from 3 to 5 RDA did not further decrease homocysteine. Percentages of patients exhibiting significant individual homocysteine decreases amounted to 43% (folic acid from 0 to 400 microg, vitamins B(12) and B(6) from 0 to 1 RDA), 14% (folic acid from 400 to 700 microg), 24% (vitamin B(12) from 1 to 3 RDA), and 18% (vitamin B(6) from 1 to 3 RDA ). The lowest plasma homocysteine at 82 weeks was 5.9 +/- 2.2 micromol/L. Patients with HbSS had higher RBC folate than HbSC. The entire group exhibited an inverse relation between RBC folate and hemoglobin. We conclude that RBC folate is less valuable for folate status assessment in SCD patients. Optimal dosages are as follows: 700 microg folic acid (3.5-7 U.S. 1989 RDA), 3 U.S. 1989 RDA vitamin B(12) (4.2-6.0 microg), and 3 U.S. 1989 RDA vitamin B(6) (4.2-6.0 mg). A practical daily combination is 1 mg folic acid (4.3-8.5 U.S. 1998 RDA when taken with meals), 6 microg vitamin B(12) (2.5-5 U.S. 1998 RDA), and 6 mg vitamin B(6) (4.6-10 U.S. 1998 RDA). This combination may by simple and relatively inexpensive means reduce these patients' inherently high risk of endothelial damage.

Adolescent↗

PubMed1999

Prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients after fortification of cereal grain flour with folic acid.

Cereal grain flour products fortified with 140 microg folic acid per 100 g flour became widely available in southeast New England by July 1997. We hypothesized that improved folate status secondary to this fortification policy would have a much more limited impact on the prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients. Between October 1997 and October 1998, fasting plasma total homocysteine (tHcy), folate and vitamin B12 levels were determined in a total of 86 renal transplant patients with stable allograft function, and 175 coronary artery disease patients whose serum creatinine was (1.4 mg/dl). All subjects lived in the Providence, RI, metropolitan area, and were either non-users of any supplements containing folic acid, vitamins B6 or B12, or had refrained from using such supplements for > or = 6 weeks. Geometric mean fasting tHcy levels were 88.0% higher (15.6 vs. 8.3 micromol/l; P < 0.001), and the prevalence of fasting tHcy levels > or = 12 microM (69.8% vs. 10.9%, P < 0.001) was markedly increased in the renal transplant patients, despite a much younger mean age and a relative preponderance of women. In the era of folic acid fortified flour, hyperhomocysteinemia is much more common in stable renal transplant versus coronary artery disease patients. As a result, renal transplant patients are a preferable high risk target population for controlled trials evaluating the tenable hypothesis that lowering total homocysteine levels will reduce cardiovascular disease outcomes.

Coronary Disease↗

PubMed2002

Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease.

AIMS: To determine the effects on homocysteine levels of two doses of folic acid compared to placebo, where the high dose is typical of that provided by pharmacological intervention and the low dose approximates that provided by dietary supplementation. METHODS AND RESULTS: The PACIFIC study was a double-blind, placebo-controlled, factorial randomized trial. Seven hundred and twenty-three individuals with a history of myocardial infarction or unstable angina were recruited from 28 clinical cardiology centres in Australia and New Zealand and randomized to folic acid 2.0 mg daily, folic acid 0.2 mg daily or placebo. The primary outcome, homocysteine, was measured using a fluorescence polarization immunoassay. Compared to placebo, 2.0 mg folic acid reduced homo-cysteine by 1.8 micromol x 1(-1) [95% confidence interval (CI) 1.3-2.3] and 0.2 mg reduced homocysteine by 1.2 micromol x 1(-1) [95% CI 0.8-1.7). The higher dose reduced homocysteine significantly more than the lower dose (P=001). CONCLUSIONS: Both doses of folic acid reduced homocysteine, but the effects of the 2.0 mg dose were about one third greater than the 0.2 mg dose. Fortification of foods with folic acid should result in population-wide lower levels of homocysteine but high-dose pharmacological supplementation would produce greater reductions for high-risk individuals.

Aged↗

PubMed2000

Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial.

BACKGROUND: A consistent finding in major depression has been a low plasma and red cell folate which has also been linked to poor response to antidepressants. The present investigation was designed to investigate whether the co-administration of folic acid would enhance the antidepressant action of fluoxetine. METHODS: 127 patients were randomly assigned to receive either 500 microg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (17 item version) score for depression of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine were carried out. RESULTS: Patients receiving folate showed a significant increase in plasma folate. This was less in men than in women. Plasma homocysteine was significantly decreased in women by 20.6%, but there was no significant change in men. Overall there was a significantly greater improvement in the fluoxetine plus folic acid group. This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 (S.D. 4. 1) in the fluoxetine plus folate group, as compared to 11.7 (S.D. 6. 7) in the fluoxetine plus placebo group (P<0.001).A percentage of 93. 9 of women, who received the folic acid supplement, showed a good response (>50% reduction in score) as compared to 61.1% of women who received placebo supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05). LIMITATIONS AND CONCLUSIONS: Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressants. Folic acid should be given in doses sufficient to decrease plasma homocysteine. Men require a higher dose of folic acid to achieve this than women, but more work is required to ascertain the optimum dose of folic acid.

Adult↗

PubMed1997

Accumulation and distribution of free folic acid content in red beet (Beta vulgaris L.).

Among vegetable plants, red beet contains a relatively high level of the B vitamin folic acid. Although many leafy green vegetables contain high levels of folic acid, red beet is consumed primarily as a root vegetable. Folic acid levels have been quantified in various vegetable plants, but little information exists regarding the accumulation and distribution of this vitamin in plant tissues. The objective of this study was to characterize free folic acid content (FFAC) in shoot and root tissue during growth of two red beet inbreds. Experiments were conducted in a greenhouse during 1993, 1994 and 1995. Two inbreds, W384 and W357, were planted in randomized complete blocks and shoot and root tissues were separately harvested at 60, 80, and 100 days after planting (DAP). Significant differences between years, tissue portions, and among harvest dates were detected, however, similar patterns in FFAC accumulation and distribution were observed between inbreds and years. FFAC in shoot tissue was significantly greater than root tissue for both inbreds. Accumulation of FFAC was linear for both inbreds across harvest dates for root tissue but not for shoot tissue. FFAC accumulation in shoot tissue increased sharply from 60 to 80 DAP but decreased sharply from 80 to 100 DAP. These results demonstrate that FFAC accumulates differentially in root and shoot tissue in a red beet plant. Maximum folic acid levels in shoot tissue are achieved prior to those in root tissue.

Folic Acid↗

PubMed1993

Low serum folic acid levels in a nursing home population: a clinical experience.

Four hundred fifty-five residents of the Wisconsin Veterans Home had fasting serum specimens obtained for folic acid as part of standard practice. Twenty-nine percent were taking folic acid supplements. Six percent (n = 28) were taking phenytoin, a folate antagonist. No resident receiving a folate supplement (400 mcg/day) had a low serum folic acid level. This finding may be important for practitioners selecting a dose of folic acid for nursing home patients. Of the 325 residents not receiving a folate supplement, nine (3%) had low folic acid levels (< 2.5 ng/mL). Two of the nine were receiving phenytoin. Five were characterized by staff as eating well. As low serum levels are preventable with a multivitamin, we believe that supplementation with a multivitamin containing 400 mcg folic acid/day should be considered in nursing home residents.

Aged↗

PubMedDate not supplied

No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia.

BACKGROUND: Mild hyperhomocysteinaemia is a cardiovascular risk factor in patients with type 2 diabetes mellitus. Homocysteine may exert its detrimental effects through induction of endothelial dysfunction and/or chronic inflammation. In this study, we examined the effects of homocysteine-lowering therapy with folic acid on biochemical markers of endothelial dysfunction and low-grade inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia (> or = 14 micromol/l). METHODS: In a randomised, double-blind, controlled trial, patients were treated with folic acid 5 mg or placebo for six months. At 0 and 6 months, albuminuria, von Willebrand factor, soluble cellular adhesion molecules, C-reactive protein, interleukin-6 and tumour necrosis factor-alpha were determined. RESULTS: Forty-one patients completed the study (folic acid 23, placebo 18). Baseline hyperhomocysteinaemia (median 17 micromol/l, range 14 to 30 micromol/l) was reduced by 29% in the folic-acid-treated group, and remained unchanged in patients receiving placebo. On average, folic acid treatment did not significantly affect any of the endothelial (e.g. von Willebrand factor: difference folic acid minus placebo +1%, confidence interval -3 to +16%) or inflammation (e.g. C-reactive protein: difference folic acid minus placebo +13%, confidence interval -42 to +52%) markers studied. Multiple regression analyses without and with adjustment for baseline differences in cardiovascular disease and ethnicity confirmed these results. An apparent beneficial effect of folic acid on albuminuria in crude analysis was attenuated by multiple adjustment (difference folic acid minus placebo -35%, confidence interval -178 to +32%, p=0.08, adjusted 0.26). CONCLUSION: The data indicate that, in this group of patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia, lowering homocysteine with folic acid for six months does not improve biochemical markers of endothelial dysfunction or low-grade inflammation.

Adult↗

PubMedDate not supplied

Folic acid treatment of hyperhomocysteinemia in peritoneal dialysis patients: no change in endothelial function after long-term therapy.

BACKGROUND: Hyperhomocysteinemia occurs in renal failure and may increase the risk for cardiovascular disease, possibly by damaging the endothelium. Folic acid and betaine are required in two separate homocysteine conversion pathways and may therefore lower plasma homocysteine. OBJECTIVE: To study the therapeutic role of betaine and the effect on endothelial function of long-term homocysteine-lowering therapy with folic acid, in peritoneal dialysis (PD) patients. PATIENTS AND DESIGN: Thirty PD patients were randomized to a 12-week treatment with 5 mg folic acid and 4 g betaine daily, or to 5 mg folic acid alone daily. They were then rerandomized to treatment with 1 or 5 mg folic acid daily for 40 weeks. MEASUREMENTS: At baseline and after 52 weeks, endothelial function was assessed by determination of endothelium-dependent vasodilatation and biochemical markers. RESULTS: Plasma total homocysteine (tHcy) was elevated at baseline: 42.6 (5.8) micromol/L. Only 1 patient (3%) had a normal plasma homocysteine (i.e., < or = 15 micromol/L) before therapy. Normalization of plasma homocysteine occurred in 39% of the patients at 12 weeks. Betaine had no additional homocysteine-lowering effect. Plasma tHcy levels were similar during treatment with 1 or 5 mg folic acid daily. Endothelial function was impaired at baseline and had not improved after 52 weeks of treatment. CONCLUSIONS: Peritoneal dialysis patients have hyperhomocysteinemia, which can be normalized with folic acid alone in about 40% of patients. Betaine does not further lower plasma homocysteine. A maintenance dose of 1 or 5 mg folic acid daily results in equivalent plasma homocysteine levels. Long-term reduction in plasma homocysteine did not result in improvement of endothelial function as assessed by our methods.

Betaine↗

PubMed2000

Folic acid protects SWV/Fnn embryo fibroblasts against arsenic toxicity.

It has been proposed that arsenic exerts its toxic effects, in part, by perturbing cellular methyl metabolism. Based on the hypothesis that folic acid treatment will attenuate the cytotoxic and growth inhibitory effects of arsenic, SWV/Fnn embryo fibroblasts were cultured in media supplemented with various concentrations of folic acid during treatment with sodium arsenite or dimethylarsinic acid (DMA). It was found that folic acid protects SWV/Fnn embryo fibroblasts from sodium arsenite and DMA cytotoxicity in a dose-dependent manner. In contrast, folic acid supplementation has no effect on toxicity resulting from treatment with ethanol or staurosporine, suggesting that folic acid is not generally protective against necrosis and apoptosis. Although folic acid protects against acute arsenic toxicity, this agent shows a modest and delayed ability to attenuate the growth inhibitory effect of arsenic on these cells. These results support a model in which perturbations of methyl metabolism contribute to the acute cytotoxicity of arsenic.

Animals↗

PubMed1998

Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration.

OBJECTIVE: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. DESIGN: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. SUBJECTS: Individual data on 1114 people included in 12 trials. FINDINGS: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P < 0.001) and at lower pretreatment blood folate concentrations (P < 0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 mumol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P < 0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. CONCLUSIONS: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 mumol/l to 8-9 mumol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.

Adult↗

PubMed1995

Leucovorin and folic acid regimens for selective expansion of murine 5,10-methylenetetrahydrofolate pools.

Mice bearing subcutaneously implanted EMT6 mammary adenocarcinoma were treated with leucovorin or folic acid by continuous subcutaneous infusion or bolus intraperitoneal injection. (6R)-5,10-Methylenetetrahydrofolate pools in cytosolic extracts of the tumor, marrow, and gut were measured by analysis of the ternary complex with thymidylate synthase (5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.1.45) and 5-fluoro-2'-deoxyuridylate, and the polyglutamate distribution in the (6R)-5,10-methylenetetrahydrofolate pool was analyzed by native gel electrophoresis. Bolus intraperitoneal administration of either leucovorin or folic acid caused dose-dependent expansion of the (6R)-5,10-methylenetetrahydrofolate pool in the tumor, but not in the marrow or gut. For example, the AUC (0-5 hr) in the tumor increased from a baseline value of 8.2 to 20 nmol/mg protein.hr after a bolus dose of 1.5 mmol/kg of leucovorin or folic acid, whereas the increase in marrow and gut was 2- to 4-fold lower. Continuous subcutaneous infusion at the same total dosage over 3 days gave AUC (0-96 hr) values of 134 nmol/mg protein.hr for controls as compared with 347 nmol/mg protein.hr for the leucovorin group and 254 nmol/mg protein.hr for the folic acid group. In contrast to bolus treatment, the increase in (6R)-5,10-methylenetetrahydrofolate in the marrow and small intestine with both leucovorin and folic acid infusion was similar to the increase in the tumor. Thus, intraperitoneal bolus injection was tumor selective, but subcutaneous continuous infusion was not. Longer-chain polyglutamates of (6R)-5,10-methylenetetrahydrofolate in the tumor after bolus treatment with 0.375 and 0.75 mmol/kg of leucovorin or folic acid increased relative to controls. At higher doses of 1.5 and 2.25 mmol/kg, an increase was observed only in the mono/diglutamate fraction. In marrow, on the other hand, the mono/diglutamate fraction, but not the longer-chain polyglutamates, increased at all doses. In the constant infusion regimen, longer-chain polyglutamates increased in all three tissues, though in gut and marrow the mono/diglutamate fraction increased more than in tumor. Leucovorin and folic acid were converted to (6R)-5,10-methylenetetrahydrofolate more efficiently but less selectively during a 3-day subcutaneous infusion than after an intraperitoneal bolus. Longer-chain polyglutamates were selectively increased in tumor by both regimens of leucovorin administration.

Animals↗