The intestinal absorption and in vivo kinetics of (6S)-[3H]-5-methyl-tetrahydrofolate (5-methyl-H4folate), (6S)-[3H]-5-formyl-H4folate and [3H]folic acid were investigated to determine whether inherent differences exist in the overall bioavailability of these folates in rats. Adult rats (n = 9 per group) were given an intragastric dose of the appropriate folate (50 pmol/100 g body wt) in 50 mmol/L ascorbate (pH 7). Each compound underwent nearly complete absorption within 8 h, and there was no significant difference in the excretion kinetics in relation to the form of folate administered. A biphasic pattern of excretion was observed over the following 8 d. Both urine and feces were important excretory routes. The rapid phase of total isotopic excretion (urinary and fecal) exhibited a half time (t1/2) of 0.11-0.12 d, whereas the t1/2 of the slower phase was 13.4-15.9 d. Isotopic distributions and the pattern of labeled folates in urine and tissues were similar regardless of the form administered. These results indicate that the bioavailability of orally administered folic acid, 5-methyl-H4folate and 5-formyl-H4folate is equivalent in rats under the conditions of this study.

Biopharmaceutics and Pharmacokinetics, An Introduction, herausgeg. von R. Notari, 285 S., Preis $13.75, Marcel Dekker Verlag, New York 1975

Folic acid, 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate exhibit equivalent intestinal absorption, metabolism and in vivo kinetics in rats.

A simple general equation is derived to show the linear plateau principle under various conditions during or after a constant or changing rate of absorption or intravenous infusion. The time required to cause a certain fraction (ft) of the total shift or change between the two steady-state plasma concentrations is equal to the time required for the cumulative (from time zero) plasma area, AUC0→t, to reach the same fraction of AUC0→∞ assumed to be obtained after an instantaneousintravenous dosing. The role of the terminal biological half-life and the importance of the earlydistribution phase and its exponential half-life or lives in the plateau principle are discussed.Clinical implications and applications to multiple dosage regimens are also discussed.

Compartment- and model-independent linear plateau principle of drugs during a constant-rate absorption or intravenous infusion

Hepatic drug metabolism in patients with acute viral hepatitis was investigated under different conditions: pregnancy, postpartum, non-pregnancy, and among males. Liver function tests were altered in all of these conditions. The relationship betweenin vivo andin vitro drug metabolism was studied in twenty-two patients using diagnostic liver needle biopsies by comparing the drug metabolising enzymes (aminopyrine-N-demethylase and bilirubin-UDP-glucuronyl transferase) in these biopsies with the elimination kinetics of antipyrine. Drug clearance tests were repeated in the patients who had recovered. All patients gave altered liver function tests results. Antipyrine half-life was significantly higher in females as compared to males. Among females, it was maximum in the pregnant group. Activities of drug metabolising enzymes were found to be significantly lower in liver biopsy material. The half-life of antipyrine showed a significant correlation with drug metabolising enzymes. After recovery patients showed a normal antipyrine half-life.

Impairment of hepatic drug metabolism in patients with acute viral hepatitis

The applications of pharmacokinetic modeling to the prediction of tissue residues of drugs in food‐producing animals are reviewed. The properties of the one‐compartment open model are discussed, and the application of this model to the serum levels, urine outputs, and tissue residues of sulfamethazine and its metabolites in sheep is described. The properties of the two‐compartment model are discussed, and the application of this model to the serum levels and urine outputs of dicloxacillin in humans is described. Complexities encountered with drugs such as pentobarbital, the tetracyclines, etidronate, and salicylate are discussed as examples of pharmacokinetic behavior that make both modeling and tissue residue prediction difficult.

Pharmacokinetic prediction of tissue residues

Eight crossbred feeder steers were used in two consecutive N balance studies to investigate the effects of infectious bovine rhinotracheitis virus (IBRV) on N kinetics. Balance Study 1, which followed a 10-d acclimation phase, consisted of 7 d of sample collection referred to as the healthy phase (d -7 to d -1). Study 2, the IBRV-infected phase, began 2 d after a nasal IBRV challenge and continued for 6 d (d 2 to d 8). A stable isotope, [15N]-glycine, was used to determine N kinetics in both studies. Steers weighed 203 kg at the beginning of the study, 208 kg at IBRV infection and 194 kg at the end of study. Infection with IBRV increased (P less than .05) urinary N excretion from 17.9 to 31.5 g/d. Daily N balance was reduced (P less than .05) during infection from 21.2 to -3.3 g/d. Total serum proteins increased (P less than .05) during infection from 6.6 to 7.1 g/100 ml, the increase being predominantly in the alpha and gamma globulin fractions. Blood urea-N increased (P less than .05) during infection from 6.5 to 12.9 mg/100 ml. The urine excretion curve of the stable isotope and the N balance data indicated that IBRV infection increased N turnover and altered tissue utilization of N.

Biopharmaceutics and Pharmacokinetics, An Introduction, herausgeg. von R. Notari, 285 S., Preis $13.75, Marcel Dekker Verlag, New York 1975

Citations

Folic acid, 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate exhibit equivalent intestinal absorption, metabolism and in vivo kinetics in rats.

Compartment- and model-independent linear plateau principle of drugs during a constant-rate absorption or intravenous infusion

Impairment of hepatic drug metabolism in patients with acute viral hepatitis

Pharmacokinetic prediction of tissue residues

Nitrogen kinetics of infectious bovine rhinotracheitis-stressed calves.

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Biopharmaceutics and pharmacokinetics;: An introduction