Anthropometric measures and their association with risk factors for cardio-metabolic diseases in Kenyan adults.

BACKGROUND: The prevalence of cardio-metabolic diseases (CMD) is drastically increasing worldwide. Anthropometric measures of fat accumulation are correlated with CMD and Metabolic Syndrome (MS), but few studies have addressed this association in sub-Saharan African populations. AIM: To investigate the association between anthropometric features, MS and other CMD risk factors in a population from Kenya. SUBJECTS AND METHODS: In this cross-sectional study including 1405 Kenyans, anthropometric measurements including visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) were carried out. Fasting blood glucose and standard oral glucose tolerance test, fasting serum insulin and plasma lipids were analysed. Homeostatic model assessment of insulin resistance was calculated. Systolic and diastolic blood pressures were measured. RESULTS: CMD risk factors and MS were associated with all anthropometric features, except for high-density lipoprotein cholesterol levels (p < 0.05). The strongest association between MS and anthropometrics was seen with SAT (ß = 1.45 ± 0.32 in men and 0.88 ± 0.14 in women, both p < 0.05). CONCLUSIONS: Anthropometric measures, especially features of central obesity such as VAT and SAT, are relevant indicators of cardio-metabolic health in Kenyan populations. SAT is the strongest predictor of MS. These results highlight the need for further research on the pathological implication of VAT and SAT, in order to understand patterns of fat distribution and cardio-metabolic health among different ethnic groups.

Modulation of inflammation by chondroitin sulfate.

OBJECTIVE AND METHODS: To evaluate the immune-modulator effect of chondroitin sulfate (CS) by means of the review of the literature. RESULTS: Inflammatory reactions are primarily originated by infectious agents, immune reactions and by sterile tissue lesions that activate membrane receptors by means of pathogen-associated molecular patterns, tissue breakdown products and cytokines. The activation of membrane receptors triggers the phosphorylation of mitogen activated protein kinases and of the nuclear factor kappaB (NF-kappaB). The binding of NF-kappaB to the promoter of target genes enhances the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase 2, phospholipase A2, and matrix metalloproteases, proteins that contribute to tissue damage and to the inflammatory reaction. The activation of NF-kappaB has a key role in the immune homeostasis and the inflammatory response and therefore, in the pathogenesis of numerous diseases. Chondroitin sulfate (CS) is able to diminish NF-kappaB activation and nuclear translocation in chondrocytes and synovial membrane, effects that may explain the benefits of CS in osteoarthritis. In addition, systemic CS reduces NF-kappaB nuclear translocation in macrophages and hepatocytes, raising the hypothesis that CS might be of benefit to treat other diseases with a strong inflammatory component. There is preliminary evidence in humans that CS improves moderate to severe psoriasis. Moreover, experimental and clinical data suggest that CS might be a useful therapeutic agent in diseases such as inflammatory bowel diseases, atherosclerosis, Parkinson's and Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis and systemic lupus erythematosus. DISCUSSION: These results urge for double blinded placebo-controlled trials to confirm the utility of CS in diseases with immune and inflammatory components.

Anti-inflammatory activity of chondroitin sulfate.

Osteoarthritis is primarily characterized by areas of destruction of articular cartilage and by synovitis. Articular damage and synovitis are secondary to local increase of pro-inflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha), enzymes with proteolytic activity (matrix metalloproteinases), and enzymes with pro-inflammatory activity (cyclooxygenase-2 and nitric oxide synthase-2). Enhanced expression of these proteins in chondrocytes and in synovial membrane appears associated to the activation and nuclear translocation of nuclear factor-kappaB (NF-kappaB). Chondroitin sulfate (CS) prevents joint space narrowing and reduces joint swelling and effusion. To produce these effects, CS elicits an anti-inflammatory effect at the chondral and synovial levels. CS and its disaccharides reduce NF-kappaB nuclear translocation, probably by diminishing extracellular signal-regulated kinase1/2, p38mitogen-activated protein kinase and c-Jun N-terminal kinase activation. This review discusses the evidence supporting that CS pleiotropic effects in chondrocytes and synoviocytes are primarily due to a common mechanism, e.g., the inhibition of NF-kappaB nuclear translocation.

Hypoxemia modifies circulating and exudate neutrophil number and functional responses in carrageenin-induced pleurisy in the rat.

To assess the effect of hypoxemia on the responses of polymorphonuclear neutrophils (PMN) during an inflammatory response, rats were maintained in a low F1O2 atmosphere (9% O2) or room air for 12 h before intrathoracic injection of carrageenin or intradermal injections of agonists. After 4 h, hypoxemic rats had 50% more circulating PMN in blood and 25% less PMN in pleural exudate, whereas the number of PMN in skin biopsies did not differ from controls. Following hypoxemia, basal adhesion of blood PMN to serum-coated plastic wells was unchanged, whereas fMLP-stimulated adhesion was 50% greater. In contrast, basal adhesion of exudate PMN was 72% greater. In hypoxemic rats, exudate PMN produced 64% more PMA-stimulated superoxide than blood PMN; furthermore, blood and exudate PMN produced 4.5- and 2-fold more LPS-stimulated nitric oxide than controls, respectively. These results show that a moderate level of hypoxemia may trigger mechanisms that will interfere with PMN emigration yet prime these cells for enhanced responses upon stimulation.

Influence of chronic obstructive lung disease on the disposition of an acidic drug (sulfamethazine).

The influence of chronic respiratory failure (CRF) on the pharmacokinetics of an acidic drug has been studied in 11 patients and in eight normal volunteers who received 10 mg/kg of oral sulfamethazine. Blood and urine samples were collected for 24 and 48 hours, respectively. No differences were observed in the rate of sulfamethazine absorption, but bioavailability was decreased when compared with control subjects. Sulfamethazine volume of distribution (Vd) was larger in patients than in control subjects. These differences in Vd may be secondary to an increase in sulfamethazine unbound fraction. No differences were observed in sulfamethazine elimination. It is concluded that in patients with CRF sulfamethazine bioavailability decreases, and Vd increases secondary to a decrease in binding. Despite the fact that plasma concentrations of the test drug will be decreased, the administration of higher doses may not be advisable.

Prazosin plasma concentration and blood pressure reduction.

Prazosin was administered to 16 patients with essential hypertension in an initial dose of 0.5 mg, after which the blood pressure (BP), pulse, and plasma concentrations of prazosin were measured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours. The dose of prazosin was then increased over 16 to 20 weeks, and similar sequences of measurements were obtained twice. Eleven patients completed the 20-week course. All patients did not respond in a similar way; two distinct patterns of BP and pulse response emerged, although there was no significant difference in the pharmacokinetic parameters, namely, absorption rate constant (Ka), maximum plasma concentration (Cpmax), time to reach the maximum concentration (Tmax), prazosin plasma half-life (T 1/2), elimination rate constant (kel), prazosin plasma concentration-time curve (AUC), and clearance. Patients in Group 1 had a marked reduction (52/30 mm Hg) of BP after the first dose of prazosin, no pulse increase, and needed a small dose of prazosin to maintain an adequate BP response. Patients in Group 3 had a minimal reduction in BP (14/13 mm Hg) after a first dose, a significant pulse increase, and needed a high dose of prazosin to control their BP. We conclude that this effect might be due to a different drug-receptor interaction, and the BP response and dose could be predicted from the response of the first dose of prazosin.

Metabolism of procainamide and p-aminobenzoic acid in patients with chronic liver disease.

Procainamide acetylation and hydrolysis, procainamide-derived p-amino-benzoic acid acetylation, and plasma hydrolysis of procaine were studied in normal volunteers and in 20 patients with chronic liver disease, Impairment of procainamide acetylation was evident in the patients, but no correlations were demonstrable between the degree of impairment and the severity of the disease. On the other hand, procainamide hydroylsis was diminished in liver disease, and as indicated by depression of serum albumin levels and plasma prothrombin activity this alteration did correlate with the degree of impairment of liver function. Procaine hydrolysis in plasma was also affected, the mean in vitro plasma half-life being prolonged in the patients with liver disease and correlating with the degree of hepatic impairment. A correlation of procainamide hydrolysis with procaine hydrolysis was also observed. Finally, acetylation of procainamide-derived p-aminobenzoic acid appeared to increase in patients with liver disease, the degree of acetylation increasing with decreasing procainamide hydrolysis capacity.

Noninvasive kinetic approach to the estimation of total hepatic blood flow and shunting in chronic liver disease--a hypothesis.

The intact hepatocyte theory of chronic liver disease suggests a relationship between the degree of shunting of total liver blood flow around the functional liver cell mass and the fraction of functional liver cell mass. By defining this relationship we have developed pharmacokinetic equations to permit the estimation of both total hepatic blood flow and the extent to which this blood flow is shunted. The method requires the determination of the systemic (hepatic) clearances of a high (e.g., indocyanine green [ICG]) and a low (e.g., antipyrine [AP]) extraction ratio drug in the same patient. Applying these equations to literature data obtained from patients with moderate or severe chronic liver disease and from patients with a surgical portacaval shunt, we find: (1) a modest decrease in total hepatic blood flow (16%) and a significant degree of shunting (27%) in patients with moderate chronic liver disease; (2) a substantially reduced total hepatic blood (52%) and extensive shunting (72%) in patients with severe chronic liver disease, and (3) a degree of shunting comparable to that estimated in patients with moderate chronic liver disease but a seriously compromised total hepatic blood flow (a reduction of 55% compared to normal) in patients with surgical portacaval shunts.

Enhancement of nadolol elimination by activated charcoal and antibiotics.

This study was carried out to assess whether nadolol undergoes enterohepatic circulation. Eight healthy subjects received 80 mg nadolol orally on three occasions at least 2 wk apart. The first experiment was a control. The second consisted of nadolol followed in 3 hr by 3 gm activated charcoal given over a 9-hr period. In the third, the subjects received 0.5 gm erythromycin base and 0.5 gm neomycin four times a day orally for 2 days before nadolol. After the activated charcoal, the nadolol AUC fell from 2455 +/- 155 to 1355 +/- 123 ng . hr/ml (mean +/- SE), as did the percentage nadolol recovered in urine (15.4 +/- 1.4 to 10.2 +/- 0.7%) and the nadolol t1/2 (17.3 +/- 1.7 to 11.8 +/- 1.6 hr). These data suggest that nonrenal elimination increased. After the antibiotics, nadolol AUC was constant, percentage of nadolol recovered in urine fell to 12.7 +/- 1.7%, nadolol t1/2 fell to 11.6 +/- 1.3 hr, and mean peak nadolol concentration rose from 146 +/- 15 to 397 +/- 52 ng/ml. These results suggest that there is an enterohepatic circulation for nadolol, that activated charcoal may decrease nadolol bioavailability, and that antibiotics may increase the nadolol effect.

Effects of phenobarbital and tobacco smoking on furosemide kinetics and dynamics in normal subjects.

This study was carried out to determine whether furosemide (F) kinetics and dynamics were influenced by phenobarbital and tobacco smoking. Our subjects were 10 normal men: five nonsmokers (NS) and five smokers (S). They received a single intravenous F injection of 40 mg. Regular serum and urine collections were made. In a second study, the NS group received 100 mg phenobarbital orally for 15 days and then a second dose of F. Cumulative 8-hr urinary excretion of sodium was identical for NS, NS with phenobarbital, and S at 345 +/- 30, 357 +/- 29, and 353 +/- 25 mmol. Diuresis was smaller by 800 ml (20%) in S than in NS. F increased endogenous creatinine clearance from 117 +/- 13 to 196 +/- 17 ml/min in NS and from 110 +/- 12 to 222 +/- 30 ml/min in NS with phenobarbital. In the S group, endogenous creatinine clearance showed a tendency to increase only slightly, from 136 +/- 23 to 180 +/- 34 ml/min. The increase in free water clearance caused by F was smaller in the S group than in the NS group (P less than 0.05). Protein binding and distribution of F were not affected by phenobarbital or tobacco smoking. F clearance was slightly higher in S than in NS, which was primarily the result of a slight increase in extrarenal F clearance. In the NS group, F clearance remained constant after phenobarbital. It is concluded that tobacco smoking in normal subjects affects the diuretic response to F without modifying kinetics.

Tixocortol pivalate, a corticosteroid with no systemic glucocorticoid effect after oral, intrarectal, and intranasal application.

Tixocortol pivalate is a corticosteroid with topical anti-inflammatory activity equal to that of hydrocortisone. It was evaluated in a group of 18 normal subjects to determine whether it exerted any systemic glucocorticoid activity after single oral or intrarectal doses and after short-term dosing by the intranasal route. Effects of tixocortol pivalate were compared to those of oral dexamethasone and intrarectal betamethasone 21-phosphate. By the three routes, tixocortol pivalate does not induce any changes in plasma cortisol, leukocyte counts (neutrophils, lymphocytes, monocytes, eosinophils), blood glucose, or 24-hr urinary excretion of sodium and potassium, whereas there were changes after dexamethasone and betamethasone. Tixocortol pivalate, however, increased urinary free cortisol-like substances. It is concluded that tixocortol pivalate given for short periods by nonparenteral routes does not induce a measurable systemic glucocorticoid effect.

Screening methods using sulfamethazine for determining acetylator phenotype.

Analysis of sulfamethazine (SMZ) kinetics in man has revealed complexities including wide intersubject variability. In our study, an attempt was made to assess the potential influence of changes in nonmetabolic parameters (absorption and urinary elimination rate constants) on the markers of acetylation capacity normally used in clinical screening procedures to determine phenotype. Seven normal subjects were classified as slow (SA) or fast acetylators (FA) according to their metabolic rate constant for SMZ (Km), plasma SMZ half-life, and percentage of N-acetyl SMZ in a 6-hr blood sample (PI6), a 5- to 6-hr urine collection (UI5--6), or a 6-hr total urine collection (UI6). Computer simulations were applied to baseline SMZ kinetic data from these subjects, varying nonmetabolic kinetic parameters over experimentally defined ranges singly, or in parallel with 1 or more of the other parameters. The simulations indicate that all the usual phenotyping procedures were sensitive to changes in absorption and urinary elimination rate constants. While these predictions require experimental confirmation, results show that the PI6 method is least sensitive to such changes, suggesting this method may minimize errors in phenotyping screening.

Mechanisms of nonlinear disposition kinetics of sulfamethazine.

Five healthy male subjects received oral doses of 10 and 40 mg/kg of sulfamethazine (SMZ) approximately 14 days apart in a nonrandomized crossover study. Blood and urine samples were collected for at least 24 and 72 hr, respectively. All samples were assayed by the Bratton-Marshall procedure for SMZ and apparent N-acetylsulfamethazine (NSMZ). Recovery of total drug (SMZ + NSMZ) in urine was 88.9% following the low and 79.5% following the high dose. The low and high dose plasma concentration time curves were not readily superimposable (i.e., nonlinear kinetic behavior was observed). The data suggest that several mechanisms contribute to the nonlinearity. Specifically, a dose-dependent decrease in absorption rate displaced the plasma concentration-time curve to the right in some subjects, whereas apparent metabolic clearance (Clm) decreased with increasing dose (estimated assuming dose = amount of SMZ + NSMZ in urine to 72 hr) in all subjects (0.35 ml/min/kg for the low and 0.23 for the high dose). Still greater dose-dependent effects were found when apparent Clm of unbound drug was determined, since free fraction rose from 0.11 to 0.30 over the observed plasma concentration range. Renal clearance (ClR) of Smz appeared to be a complex function of time. In the low dose study it ranged from an average of 0.071 ml/min/kg at 2 hr to 0.146 ml/min/kg at 6 hr after drug. After the high dose comparable values were 0.083 and 0.128. Interindividual variability and pronounced nonlinear kinetics of SMZ after 40 mg/kg suggest that this dose is probably a poor choice for the determination of acetylator phenotype.

Nonlinear kinetics and pharmacologic response to mibefradil.

BACKGROUND: Increasing oral doses of mibefradil (10 to 320 mg) decrease its apparent oral clearance; however, intravenous doses up to 80 mg do not reduce its systemic clearance. This study aimed to understand the mechanisms underlying the zero-order kinetics of mibefradil. METHODS: A group of 10 normotensive volunteers received 50 mg/day oral mibefradil for 8 days and, on days 1 and 8, 5 mg deuterated mibefradil by infusion. Ten additional volunteers observed the same protocol with a daily oral dose of 100 mg mibefradil. Serial blood samples were withdrawn, and mibefradil plasma concentrations were assayed by liquid chromatography-mass spectrometry. Blood pressure and heart rate were measured for 4 hours, and an ECG was performed 2 hours after drug administration. RESULTS: Repeated oral administration of 50 mg mibefradil generated zero-order kinetics secondary to a decrease in mibefradil systemic clearance. Compared with the 50-mg dose, single and repeated oral doses of 100 mg further decreased mibefradil clearance. Mibefradil bioavailability was not affected by increasing mibefradil doses. Mean diastolic blood pressure was decreased by single and repeated doses of 100 mg to the same extent. Repeated doses of 100 mg reduced heart rate and prolonged the PR and QTc, changes that were associated with mibefradil plasma concentrations. CONCLUSIONS: Repeated doses of 50 mg or doses of 100 mg mibefradil generated zero-order kinetics secondary to a decrease in hepatic extraction of the drug. Zero-order kinetics did not affect the response-concentration relationship of mibefradil.

Tocainide kinetics and metabolism: effects of phenobarbital and substrates of glucuronyl transferase.

Tocainide, a lidocaine congener with low hepatic clearance, is eliminated predominantly by formation of a novel glucuronide conjugate. This suggested the possibility of metabolic interactions with enzyme inducers or competitive substrates for glucuronyl transferase. The time course of tocainide blood concentration as well as the urinary excretion-time profiles of drug and principal metabolite (a glucuronide of tocainide carbaminic acid, TOCG) were examined in six subjects before and after 15 days on phenobarbital (100 mg/day). In another study, the effect of salicylamide and clofibrate on the time courses of tocainide and TOCG urinary excretion were examined in four of the same six subjects. After 600 mg tocainide HCl by mouth, the area under the tocainide blood concentration-time curve was 48.2 +/- 11.9 hr micrograms/ml for the control dose and 49.6 +/- 4.2 hr micrograms/ml (mean = SD) after phenobarbital. Percent of dose excreted unchanged in urine (46.0 +/- 4.9 and 43.4 +/- 5.6) and percent of dose excreted as TOCG (30.6 +/0 3.3 and 27.7 +/- 7.2) were not affected by phenobarbital (data presented as control and after phenobarbital). Because salicylamide has been reported to be a potent inhibitor of the glucuronidation of some drugs and because clofibrate yields metabolites that may be competitive inhibitors of tocainide conjugation, the two were given together with tocainide. Average percent of dose recovered in urine as unchanged tocainide in 24 hr was 26.8%, 28.3%, and 29.7% in the control, salicylamide, and clofibrate studies. The urinary excretion of TOCG was also not affected. It is concluded that under the conditions of our investigation, the principal urinary metabolite of tocainide, a glucuronide of tocainide carbaminic acid, is formed by a mechanism not subject to induction by phenobarbital or competitive inhibition by salicylamide or clofibrate.

Effect of aminoglycosides on the disposition of thyroid hormones and thyroglobulin.

Our study was designed to confirm the potential effects of three aminoglycosides on the disposition of thyroid hormones. Twenty-seven patients diagnosed with either cellulitis (n = 19), chronic osteitis (n = 4), or an abscess (n = 4) were selected. Thirteen patients received tobramycin, 60 to 100 mg iv q. 8 h., plus cloxacillin, 1 gm iv q. 4 h.; seven patients received netilmicin, 40 to 120 mg iv q. 8 h., plus cloxacillin, 1 gm iv q. 4 h.; and seven patients received either cloxacillin, 1.5 gm iv q. 4 h., or cefoperazone, 2 to 4 gm iv q. 12 h. for at least 7 days. Another group of six normal subjects received neomycin, 0.5 gm po q. 6 h. for 7 days. All these subjects had normal thyroid function before antibiotic dosing and none had thyroid function abnormalities. Tobramycin and cloxacillin/cefoperazone did not influence thyroid function. Netilmicin decreased the total serum concentrations of triiodothyronine (T3) from 114 +/- 9 to 75 +/- 7 ng/dl (P less than 0.01), probably because of increased clearance, as the T3 free fraction increased from 0.43% +/- 0.02% to 0.49% +/- 0.02% (P less than 0.05). Thyroxine (T4) and reverse T3 (rT3) levels were not affected. Neomycin decreased T3 levels from 104 +/- 8 to 92 +/- 7 ng/dl (P less than 0.05) and the serum concentrations of thyroglobulin from 17.3 +/- 2.0 to 11.7 +/- 2.0 ng/ml (P less than 0.001). Because T4 and rT3 levels did not change, our results suggest that neomycin may have directly affected the gland. We conclude that some aminoglycosides can alter the disposition of thyroid hormones.

Effect of hypoxia on cytochrome P450 activity and expression.

In the last three decades, numerous reports have shown that patients with chronic pulmonary disease and with heart failure with hypoxemia cleared drugs at a lower rate than healthy volunteers. As a consequence decreased clearance, drug toxicity is frequent in these patients. The reduction in drug clearance is due to a decrease in activity of cytochrome P450 isoforms, partly associated to the hypoxemia. With in vivo animal models, acute moderate hypoxia (PaO2 of around 35-50 mm Hg) reduces the clearance of drugs biotransformed by CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2E1, although hypoxia does not affect the clearance of drugs biotransformed by CYP3A6. Ex vivo and in vitro experiments demonstrate that hypoxia down-regulates CYP1A1, CYP1A2, CYP2B6, CYP2C9 and CYP2C19, decrease preceded by a reduction in activity. On the other hand, acute moderate hypoxia up-regulates CYP3A6. The changes in protein expression are preceded by modifications in the mRNA coding for the proteins. The effect of hypoxia on hepatic cytochrome P450 is carried out by serum mediators, e.g. interferon-gamma, interleukin-1beta, and interleukin-2 are responsible for the decrease in activity and in expression of cytochrome P450 isoforms, and erythropoietin accounts for the increase in CYP3A6. Probably several mechanisms underlie and contribute to the decrease in activity and down-regulation of cytochrome P450 isoforms by hypoxia, e.g. reducing potentiation factors, inducing repressor elements and activating negative regulatory elements. The up-regulation of CYP3A6 implies a PTK- and p42/44MAPK-dependent stabilization/activation, nuclear translocation of HIF-1 and AP-1, binding to CYP3A6 promoter, and transactivation of the gene to induce CYP3A6 expression.

Isoniazid for tremor in multiple sclerosis: a controlled trial.

We evaluated the effects of isoniazid on tremor in 13 patients with MS. Patients were evaluated before treatment, after 1 month of therapy (1,000 mg daily), and 1 month after the last dose. Ten patients improved on at least one of three methods of evaluation. Transient side effects were common, possibly because there was a high percentage of "slow acetylators"; dosage was reduced by one-half in five patients. Improvement was mild and did not result in significant functional improvement.

Effects of food and sucralfate on the pharmacokinetics of naproxen and ketoprofen in humans.

Compliance to nonsteroidal anti-inflammatory drug therapy can be compromised by gastrointestinal side effects. To overcome this problem, food, antacid, or sucralfate are often co-administered with nonsteroidal anti-inflammatory drugs. Three studies were conducted on three groups of 12 volunteers in order to determine the influence of food or sucralfate on the pharmacokinetics of naproxen and ketoprofen. In a crossover experimental design, the first group received a single dose (50 mg) of ketoprofen with and without sucralfate (2 g). The second group received single (100 mg) and multiple (100 mg twice daily for 5 days) doses of enteric-coated ketoprofen with and without food. The third group received single (500 mg) and multiple (500 mg twice daily) doses of naproxen with and without sucralfate. Multiple blood samples were drawn and analyzed by high-pressure liquid chromatography. Short- and long-term pharmacokinetic parameters were determined. Results in group 1 showed that neither ketoprofen bioavailability nor maximal plasma concentration and time to reach maximal concentration were affected by the administration of sucralfate. However, in group 2 absorption of ketoprofen was markedly affected by food. In the presence of food, maximal plasma concentration decreased from 10.7 to 6.3 micrograms/ml after single-dose administration and 12.1 to 8.0 micrograms/ml after multiple-dose administration. The time to reach maximal plasma concentration was also modified by food, increasing from 2.8 to 7.1 hours after single-dose and 2.8 to 7.6 hours after multiple-dose administration. Food caused a significant decrease in the bioavailability of ketoprofen (over 40 percent) following both single-dose (23.8 versus 13.1 micrograms.hour/ml) and multiple-dose (29.3 versus 16.8 micrograms.hour/ml) administration. Results obtained in group 3 showed that sucralfate reduced the absorption rate constant of naproxen, from 1.7 to 1.2 hours-1 and from 1.5 to 0.7 hour-1 following single- and multiple-dose administration, respectively. However, bioavailability of naproxen was not affected by sucralfate administration. Overall, these studies have shown that sucralfate does not alter the pharmacokinetics of naproxen and ketoprofen; the amount of drug absorbed remains constant. However, plasma concentrations of ketoprofen after single- and multiple-dose administration were greatly affected by food, with a decrease of greater than 40 percent in bioavailability.