54Mn absorption and excretion in rats fed soy protein and casein diets.

Rats were fed diets containing either soy protein or casein and different levels of manganese, methionine, phytic acid, or arginine for 7 days and then fed test meals labeled with 2 microCi of 54Mn after an overnight fast. Retention of 54Mn in each rat was measured every other day for 21 days using a whole-body counter. Liver manganese was higher (P less than 0.0001) in soy protein-fed rats (8.8 micrograms/g) than in casein-fed rats (5.2 micrograms/g); manganese superoxide dismutase activity also was higher in soy protein-fed rats than in casein-fed rats (P less than 0.01). There was a significant interaction between manganese and protein which affected manganese absorption and biologic half-life of 54Mn. In a second experiment, rats fed soy protein-test meals retained more 54Mn (P less than 0.001) than casein-fed rats. Liver manganese (8.3 micrograms/g) in the soy protein group was also higher than that (5.7 micrograms/g) in the casein group (P less than 0.0001), but manganese superoxide dismutase activity was unaffected by protein. Supplementation with methionine increased 54Mn retention from both soy and casein diets (P less than 0.06); activity of manganese superoxide dismutase increased (P less than 0.05) but liver manganese did not change. The addition of arginine to casein diets had little effect on manganese bioavailability. Phytic acid affected neither manganese absorption nor biologic half-life in two experiments, but it depressed liver manganese in one experiment. These results suggest that neither arginine nor phytic acid was the component in soy protein which made manganese more available from soy protein diets than casein diets.

Application of propranolol to the keratinized oral mucosa: avoidance of first-pass elimination and the use of 1-dodecylazacycloheptan-2-one (Azone) as an absorption enhancer of bioadhesive film-dosage form.

The bioavailability of propranolol applied to the oral mucosa was examined in the hamster. The capacity of hamster cheek pouch, used as a model of keratinized oral mucosa, to metabolize propranolol in vitro is enormously lower than that of the liver. Significant amounts of propranolol absorbed from the small intestine were metabolized to naphthoxylactic acid and 4-hydroxypropranolol (4HP) during the passage through the intestinal wall, and then the greater portion of unchanged propranolol and almost all 4HP were subsequently metabolized by hepatic first-pass elimination in vivo. The systemic bioavailabilities of propranolol after the intra-small-intestinal loop and the intra-cheek-pouch administrations were 8.4% and 88.5%, respectively. The bioavailability of propranolol was improved further (to 97.1%) by a 1-h pretreatment of the cheek pouch with 5% 1-dodecylazacycloheptan-2-one (Azone)-emulsion. Bioadhesive film-dosage forms of propranolol were prepared with hydroxypropylcellulose. Both the in vitro permeation and the in vivo absorption of propranolol across the cheek pouch were enhanced by the incorporation of Azone to the film-dosage form.

Mechanisms underlying the differential effects of ethanol on the bioavailability of riboflavin and flavin adenine dinucleotide.

Chronic alcoholism is associated with a high prevalence of riboflavin deficiency. Experiments were designed in an animal model to determine whether ethanol alters selectively the absorption of riboflavin and flavin adenine dinucleotide (FAD), the predominant dietary form of the vitamin. Rats received by gavage a liver homogenate to which either [14C]riboflavin or [14C]FAD was added with either ethanol or isocaloric sucrose solutions. Ethanol markedly diminished the bioavailability of [14C]FAD to a greater degree than that of [14C]riboflavin. Corroboration of an ethanol-impaired intraluminal hydrolysis of FAD was provided by using everted jejunal segments and measuring mucosal uptake of [14C]riboflavin together with nonradiolabeled FAD. In subsequent studies with mucosal cell extracts, ethanol markedly inhibited activities of FAD pyrophosphatase and flavin mononucleotide (FMN) phosphatase. These findings suggest that dietary sources of riboflavin (FMN and FAD) are not absorbed as well in the presence of ethanol than are vitamin preparations containing riboflavin, which is utilized more readily.

Effects of purified dietary fiber sources on beta-carotene utilization by the chick.

Effects of various purified dietary fiber components on beta-carotene utilization by the chick were investigated in two experiments (expt.). Eight-day-old Columbian X New Hampshire male (expt. 1) or female (expt. 2) chicks were fed a vitamin A-deficient diet for 1 wk and then fed beta-carotene-supplemented diets containing 0% fiber, 7% arenaceous flour or 7% of a purified fiber source for 4 wk. Results of expt. 1 showed that hemicellulose, lignin and citrus pectin, but not arenaceous flour or polygalacturonic acid, depressed beta-carotene utilization by the chick, as measured by percentage of consumed beta-carotene stored in liver as vitamin A relative to the 0% fiber control. In expt. 2, effects of the methoxyl content of pectin were studied. High and medium methoxyl apple pectin, citrus pectin and polygalacturonic acid reduced storage of vitamin A in liver. Low methoxyl apple pectin had no significant effect on beta-carotene utilization. Thus, several purified forms of dietary fiber significantly reduced beta-carotene utilization by chicks when fed at the 7% supplementary level. Moreover, with pectin, there was an inverse relationship between methoxyl content of pectin and beta-carotene utilization.

Bioavailability of paracetamol after oral administration to healthy volunteers. Influence of caffeine on rate and extent of absorption.

The absorption rate and the bioavailability of two commercially available paracetamol tablets were investigated in a panel of seven volunteers; one of these tablets contained a combination of 50 mg caffeine and paracetamol. Considering the urinary excretion data, it is concluded that the tablets release their contents completely; the absolute bioavailability, however, calculated from plasma concentrations, is lower than 100%, indicating a first-pass effect. A marked interindividual variation in first-pass effect was noticed. No general influence of caffeine on the extent of absorption of paracetamol could be established; there is, however, a slightly positive influence of caffeine on the absorption rate of paracetamol in six out of seven volunteers. It was concluded that this positive influence on absorption rate is not responsible for the established enhancement of paracetamol analgesia by caffeine.

The pharmacology of orally administered chemotherapy. A reappraisal.

Rational treatment of pediatric malignancies requires a detailed knowledge of the clinical pharmacology of those antineoplastic agents used therapeutically. A number of different agents are administered by the oral route. Recently, the clinical pharmacology of 6-mercaptopurine (6-MP) and methotrexate (MTX), the two agents that are the mainstay of maintenance chemotherapy in acute lymphoblastic leukemia (ALL), were investigated. Studies of oral 6-MP indicate that, contrary to previous information, the bioavailability of this drug is relatively poor after oral administration, and that plasma 6-MP concentrations achieved after uniform oral dosing are highly variable. Similarly, study of the pharmacology of orally administered MTX indicates that there is little correlation between MTX dose and the peak serum level achieved. These findings suggest that some patients may not be exposed to adequate systemic concentrations of 6-MP and/or MTX after oral administration, and raise the possibility that the development of relapse in some patients with ALL may be the result of a pharmacologic failure of oral maintenance therapy. A comprehensive prospective study of the clinical pharmacology of MTX and 6-MP in patients with ALL undergoing maintenance chemotherapy is currently in progress.

Cimetidine absorption in humans during sucralfate coadministration.

Cimetidine absorption after a single 300 mg oral dose was evaluated in six normal subjects in the absence or presence of sucralfate. Sucralfate was ingested four times a day for 2 days prior to and for two additional doses on the day of cimetidine ingestion. Sucralfate coadministration had no statistically significant influence on the rate or extent of cimetidine absorption.

Casein phosphopeptide (CPP) enhances calcium absorption from the ligated segment of rat small intestine.

A casein phosphopeptide (CPP) was prepared from beta-casein of cow's milk and the effect of this peptide on the absorption of calcium from a ligated segment of rat small intestine was investigated. CPP injected into a ligated loop of rat small intestine enhanced absorption of calcium from the loop and augmented the deposition of calcium in the femur. Furthermore, CPP inhibited the precipitation of calcium phosphate in vitro, suggesting that this peptide enhances calcium absorption from the small intestinal lumen by increasing the concentration of soluble calcium. This new evidence confirms our previous hypothesis that CPP is an important factor in raising the availability of calcium in milk.

The effect of ranitidine on the disposition of lignocaine.

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady-state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.

The effect of antacid and aspirin on the bioavailability of isofezolac in man.

Bioavailability of isofezolac, a new non-steroid anti-inflammatory drug, with or without antacid and aspirin coadministration was investigated in 6 healthy volunteer. Each subject received, in random order, isofezolac (50 mg) alone or associated with aspirin (1 g) or phosphalugel (11 g aluminum phosphate). Isofezolac plasma concentrations were salicylic acid by spectrofluorimetric method. Plasma protein binding of drugs was studied by dialysis equilibrium method. During the absorption phase isofezolac plasma levels were slightly decreased in association with isofezolac-aspirin, but bioavailability of isofezolac was not modified. Time to peak of isofezolac was comparable in the three treatments, as was the case with plasma half-lives. Aluminum phosphate did not modify isofezolac availability. Plasma protein binding of isofezolac was very high (99%) and did not influence salicylic acid binding.

Imipramine disposition in users of oral contraceptive steroids.

Ten women on long-term, low-dose estrogen oral contraceptive steroids (OCS) and eight age-matched drug-free female controls received an intravenous infusion of 12.5 mg imipramine. Eleven (six OCS users and five controls) also took a 50-mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OCS and control groups and clearance was of the same order (899 and 975 ml/min). Elimination t1/2 was prolonged in OCS users after intravenous doses (17.8 vs 25.5 hr) but did not change after oral doses (18.4 vs 19.1 hr). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OCS users (from 27.1% vs 44.1%), which resulted in a trend toward decreased apparent oral clearance (from 4649 vs 2322 ml/min). Women who used OCS regularly show little change in imipramine kinetics after intravenous dosing. After oral dosing absolute systemic bioavailability increased, resulting in decreased apparent oral clearance in the absence of any change in oral elimination t1/2. Imipramine (with high first-pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These data are consistent with OCS inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OCS use.

PIP: 10 women on longterm, low dose estrogen oral contraceptives (OCs) and 8 age matched drug free female controls received an intravenous infusion of 12.5 mg imipramine. 11 (6 OC users and 5 controls) also took a 50 mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OC and control groups and clearance wa of the same order (899 and 975 ml/minute). Elimination 1/2-life was prolonged in OC users after intravenous doses (17.8 vs 25.5 hours) but did not change after oral doses (18.4 vs 19.1 hours). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OC users (from 27.1% vs 44.1%), which resulted in a trend towards decreased apparent oral clearance (from 4649 vs 2322 ml/minute). Women who used OCs regularly showed little change in imipramine kinetics after intravenous dosing. After oral dosing, absolute systemic bioavailability increased, resulting in decreased apparent oralclearance in the absence of any change in oral elimination 1/2-life. Imipramine (with high 1st pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These date are consistent with OC inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OC use.

Effect of antacid on the bioavailabiity of lithium carbonate.

The effect of an antacid on the bioavailability of lithium carbonate was determined in six healthy men in a crossover study. The volunteers were given single 300-mg doses of lithium carbonate alone and with 30 ml of an antacid containing aluminum and magnesium hydroxides with simethicone. Blood samples were collected at various times for 0-24 hours after each dose. The plasma samples were analyzed for lithium using a spectrophotometer, and bioavailability variables were calculated from plasma lithium concentration-time curves. There were no significant differences in peak plasma lithium concentration, time to peak concentration, area under the concentration-time curve from 0 to 24 hours, first-order absorption rate constant, and first-order elimination rate constant between the two treatments. Concurrent administration of antacids and lithium carbonate should not affect lithium blood concentrations.

The absence of effect of azathioprine on prednisolone pharmacokinetics following maintenance prednisone doses in kidney transplant patients.

Kidney transplant patients receive chronic prednisone and azathioprine for immunosuppression. However, the effect of azathioprine on prednisolone pharmacokinetics has not been determined in this population. Total and unbound prednisolone concentrations were determined, using high performance liquid chromatography and equilibrium dialysis, in eight kidney transplant patients following their usual oral maintenance dose of prednisone alone and concomitantly with their usual dose of azathioprine. The results showed no significant differences between the two groups in estimates of prednisolone plasma protein binding parameters and peak time, peak concentration, mean input time, clearance/F, volume of distribution/F, or half-life (t 1/2), using total or unbound prednisolone concentrations. Thus, the concomitant administration of azathioprine does not appear to alter the bioavailability or elimination of prednisolone at these doses.