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PubMed1989

Interaction between oral ciprofloxacin and caffeine in normal volunteers.

The influence of multiple doses of ciprofloxacin on the disposition of caffeine and its major metabolite, paraxanthine, was investigated in healthy volunteers. Ten xanthine-free, fasting males were given 100 mg of caffeine orally 24 h before being given ciprofloxacin and again with the third dose of ciprofloxacin (750 mg administered every 12 h). Blood samples were serially collected after both doses of caffeine and after the first and last doses of ciprofloxacin. Ciprofloxacin significantly increased the half-life of caffeine (from 5.2 +/- 1.2 to 8.2 +/- 2.5 h) and the area under the caffeine concentration-time curve (from 16.3 +/- 6.6 to 25.9 +/- 7.8 micrograms.h/ml) while decreasing the total body clearance (from 106 +/- 41.6 to 58.2 +/- 28.8 ml/min per 1.73 m2). In addition, the rate of conversion of caffeine to paraxanthine was significantly delayed. There was no significant linear correlation between the urinary recovery of oxociprofloxacin at 0 to 12 h and the change in the area under the caffeine concentration-time curve. There was also a small but statistically significant increase in the area under the ciprofloxacin concentration-time curve during simultaneous administration of caffeine. We concluded that ciprofloxacin causes a significant increase in the half-life of caffeine and in the area under the caffeine concentration-time curve by reducing total body clearance. This interaction is due at least in part to a delay in the conversion of caffeine to paraxanthine. The clinical significance of these observations remains to be determined. Lastly, caffeine may alter the kinetics of ciprofloxacin, a possibility which should be more fully explored.

Adult↗
PubMed1989

Role of calcium in caffeine-norepinephrine interactions in cardiac Purkinje fibers.

Caffeine-norepinephrine interactions were studied in canine cardiac Purkinje fibers perfused in vitro. Caffeine (0.5-1 mM) or theophylline (0.5-1 mM) increased and then decreased contractile force in the absence and presence of 0.5-10 microM norepinephrine (NE) [in high extracellular calcium concentration ([Ca]o) caffeine only decreases force]. Occasionally, caffeine only decreased force in the presence of NE. In the presence of NE and 12 mM (sometimes even 4 mM) extracellular potassium concentration, caffeine did not decrease force below the precaffeine level. Reciprocally, in 0.5-2 mM caffeine NE increased force, although less than in the absence of caffeine. Even in 9 mM caffeine, NE increased force but slowed the final phase three repolarization of the action potential. Both NE and 8.1 mM [Ca]o increased force, but NE decreased force in the presence of high [Ca]o. In NE and propranolol (or propranolol alone), caffeine only increased force, whereas it had the usual effects in the presence of methoxamine or phenotolamine. In the presence of iodoacetic acid and 2-deoxy-D-glucose, NE caused contracture and caffeine exaggerated it. In contrast, in NE and 2 mM Mn, caffeine only increased force. It is concluded that initially NE diminishes the cytoplasmic calcium overload induced by caffeine (by promoting Ca uptake into the sarcoplasmic reticulum) and subsequently enhances it (by increasing the slow inward current).

Animals↗
PubMed1998

Effect of caffeine on metabolism, exercise endurance, and catecholamine responses after withdrawal.

In this study the effects of acute caffeine ingestion on exercise performance, hormonal (epinephrine, norepinephrine, insulin), and metabolic (free fatty acids, glycerol, glucose, lactate, expired gases) parameters during short-term withdrawal from dietary caffeine were investigated. Recreational athletes who were habitual caffeine users (n = 6) (maximum oxygen uptake 54.5 +/- 3.3 ml x kg-1 x min-1 and daily caffeine intake 761.3 +/- 11.8 mg/day) were tested under conditions of no withdrawal and 2-day and 4-day withdrawal from dietary caffeine. There were seven trials in total with a minimum of 10 days between trials. On the day of the exercise trial, subjects ingested either dextrose placebo or 6 mg/kg caffeine in capsule form 1 h before cycle ergometry to exhaustion at 80-85% of maximum oxygen uptake. Test substances were assigned in a random, double-blind manner. A final placebo control trial completed the experiment. There was no significant difference in any measured parameters among days of withdrawal after ingestion of placebo. At exhaustion in the 2- and 4-day withdrawal trials, there were significant increases in plasma norepinephrine in response to caffeine ingestion. Caffeine-induced increases in serum free fatty acids occurred after 4 days and only at rest. Subjects responded to caffeine with increases in plasma epinephrine (P < 0.05) at exhaustion and prolonged exercise time in all caffeine trials compared with placebo, regardless of withdrawal from caffeine. It is concluded that increased endurance is unrelated to hormonal or metabolic changes and that it is not related to prior caffeine habituation in recreational athletes.

Administration, Oral↗
PubMed2004

Caffeine inhibits cell proliferation by G0/G1 phase arrest in JB6 cells.

Caffeine is a major biologically active constituent in coffee and tea. Because caffeine has been reported to inhibit carcinogenesis in UVB-exposed mice, the cancer-preventing effect of caffeine has attracted considerable attention. In the present study, the effect of caffeine in quiescent (G0 phase) cells was investigated. Pretreatment with caffeine suppressed cell proliferation in a dose-dependent manner 36 h after addition of fetal bovine serum as a cell growth stimulator. Analysis by flow cytometry showed that caffeine suppressed cell cycle progression at the G0/G1 phase, i.e., 18 h after addition of fetal bovine serum, the percentages of cells in G0/G1 phase in 1 mM caffeine-treated cells and in caffeine-untreated cells were 61.7 and 29.0, respectively. The percentage of cells in G0/G1 phase at 0 h was 75.5. Caffeine inhibited phosphorylation of retinoblastoma protein at Ser780 and Ser807/Ser811, the sites where retinoblastoma protein has been reported to be phosphorylated by cyclin-dependent kinase 4 (cdk4). Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner. However this compound did not directly inhibit the activity of this complex. In addition, caffeine did not affect p16INK4 or p27Kip1 protein levels, but inhibited the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3beta. Our results showed that caffeine suppressed the progression of quiescent cells into the cell cycle. The inhibitory mechanism may be due to the inhibition of cell growth signal-induced activation of cdk4, which may be involved in the inhibition of carcinogenesis in vivo.

Animals↗
PubMed2002

Effect of zinc ions on caffeine-induced contracture in vascular smooth muscle and skeletal muscle of rat.

The effect of zinc ions on caffeine-induced contracture in vascular smooth muscle and skeletal muscle of rat was studied. In aortic strips, caffeine contracture was depressed by Zn2+ in a dose-dependent manner. Moreover, the extent of the depression of caffeine contracture in the Zn2+ loaded smooth muscle increased with repetitive caffeine exposures. For instance, in the preparations perfused with a medium containing 100 microM [Zn2+] for 15 or 30 min, the first caffeine contractures were similarly depressed to about 60% of the control. However, the subsequent caffeine exposure at 15 min interval could not evoke any contracture. In this study this feature is referred to as activation dependence of the Zn2+ effect. In small bundles of soleus muscle 2ñ100 microM [Zn2+] similarly caused a depression of caffeine contracture, and the activation dependence also was evident. However, an evident potentiation of caffeine contracture was seen in the preparations loaded with lower [Zn2+] such as 0.5 microM, indicating that the effect of Zn2+ on caffeine contracture of skeletal muscle was somewhat different from that seen in smooth muscle. By observing how the depression effect depends on the intervals between caffeine exposures as well as on caffeine concentrations, it is indicated that the activation dependence of the Zn2+ effect, at least in skeletal muscle, may not be explained by depletion of intracellular Ca2+ stores alone. The possible mechanism for that caffeine contracture of smooth muscle and skeletal muscle was differentially affected by Zn2+ ions is discussed.

Animals↗
PubMed1999

Caffeine intake, tolerance, and withdrawal in women: a population-based twin study.

OBJECTIVE: Caffeine is by far the most commonly consumed psychoactive substance. The use and abuse of most other licit and illicit psychoactive drugs have been shown to be substantially heritable. However, the impact of genetic factors on caffeine consumption, heavy use, intoxication, tolerance, and withdrawal is largely unknown. METHOD: Caffeine consumption, in the form of brewed coffee, instant coffee, tea, and caffeinated soft drinks, as well as caffeine intoxication, tolerance, and withdrawal, were assessed by personal interviews of 1,934 individual twins from female-female pairs ascertained from the population-based Virginia Twin Registry. The sample included both members of 486 monozygotic and 335 dizygotic pairs. Twin resemblance was assessed by probandwise concordance, odds ratios, and tetrachoric correlations. Biometrical model fitting was also performed. RESULTS: The resemblance in twin pairs for total caffeine consumption, heavy caffeine use, caffeine intoxication, caffeine tolerance, and caffeine withdrawal was substantially greater in monozygotic than in dizygotic twin pairs. Model fitting suggested that twin resemblance for these measures could be ascribed solely to genetic factors, with estimated broad heritabilities of between 35% and 77%. CONCLUSIONS: Caffeine is an addictive psychoactive substance. Similar to previous findings with other licit and illicit psychoactive drugs, individual differences in caffeine use, intoxication, tolerance, and withdrawal are substantially influenced by genetic factors.

Adult↗
PubMed2001

Caffeine metabolism in premature infants.

Caffeine has been used frequently in the treatment and prevention of apnea of prematurity. The metabolism of caffeine depends on the activities of the hepatic enzymes that vary from one infant to another. The objective of this study was to determine the influence of postnatal age (PNA), birth weight (BW), study weight (SW), gestational age (GA), postconceptual age (PCA), and gender on the maturation of caffeine metabolism in premature infants. The caffeine base was administered orally as a loading dose of 10 mg/kg, followed by a maintenance dose of 2 mg/kg every 24 hours. The steady-state concentration of caffeine and metabolites was measured in plasma taken on the 5th-day postloading dose. The molar concentration ratios for the N3 (N3-), N7 (N7-), N1 (N1-), and all methyl (Nall-) demethylation processes; clearance (CL); and the percentage of molar concentration of caffeine found in plasma to that of the total caffeine and metabolites (%CAF) were calculated from samples collected from 80 neonatal infants. The 48 male and 32 female premature infants had median (range) BW (g), GA (weeks), SW (g), PCA (weeks), and PNA (days) of 1300 (650-2260), 30 (24-34), 1630 (980-2670), 34 (29-40), and 28 (5-60), respectively. The median (range) of the ratios for the %CAF, CL, and the N3-, N7-, N1-, and Nall- were 86.9 (52.9-99.0), 0.127 (0.046-0.503) ml.kg-1.min-1, 0.032 (0-0.438), 0.070 (0.007-0.471), 0.026 (0-0.283), and 0.0463 (0.003-0.303), respectively. When the patients were stratified into four PNA age groups, each older group showed a consistently higher level of caffeine metabolic activity for the N3-, N7-, and Nall- pathways with a corresponding decrease in the %CAF, whereas no significant differences were seen for the N1-pathway or for CL. No pattern of significant differences between the demethylation process ratios, %CAF, or CL was seen between groups of infants when they were stratified according to BW, SW, PCA, or GA. The female infants were found to have significantly higher rates of caffeine metabolism as shown by %CAF, N1-, N3-, and Nall- processes but not the N7-. Multivariate linear regression analysis by two methods demonstrated that PNA is significantly related to %CAF and Nall-, whereas the female patients had higher levels of metabolic activity for the %CAF and N1- process. The authors conclude that the N7-demethy-lation process is the predominate caffeine metabolic process in premature infants. Furthermore, the maturation of the caffeine metabolism in premature infants with a PNA of less than 60 days increases with postnatal age, regardless of birth weight, gestational age, postconceptual age, and study weight. The female neonatal patients demonstrated a higher rate of caffeine metabolism than the males.

Age Factors↗
PubMed1999

Effect of caffeine on ibuprofen-induced gastric mucosal damage in rats.

During investigations on the effect of caffeine on ibuprofen-induced gastric mucosal lesions in rats, we have found that caffeine (p.o.) inhibits the development of ibuprofen-induced gastric lesions in a dose-dependent manner (ED50 18.4 mg kg(-1)). To investigate this protective effect of caffeine, we have studied the effect of caffeine on HCl-ethanol-induced gastric mucosal lesions with or without indomethacin pretreatment. Caffeine inhibited the development of HCl-ethanol-induced gastric lesions with and without indomethacin pretreatment. These results indicate that caffeine did not act as a mild irritant but, on the contrary, had protective effects. We measured the gastric mucosal prostaglandin E2 (PGE2) concentrations and gastric mucosal blood flow, as representative protective factors for gastric mucosa. Caffeine did not affect the gastric mucosal PGE2 concentrations 4h after administration of ibuprofen. However, topical administration of caffeine resulted in an increase in gastric mucosal blood flow, as measured by laser Doppler flowmetry. We investigated the gastric acid secretion and gastric mucosal myeloperoxidase activity as representative aggressive factors for gastric mucosa. When caffeine was administered intraduodenally in pylorus-ligated rats, gastric acid secretion decreased in a dose-dependent manner, with an ED50 of 44.9 mg kg(-1). Caffeine decreased ibuprofen-induced gastric myeloperoxidase activity in a dose-dependent manner, with an ED50 of 9.1 mg kg(-1). These findings indicate that caffeine, at least in rats, may inhibit the development of acute gastric mucosal injury. The mechanisms underlying the protective actions of caffeine are unclear, but may be related in part to an increase in gastric mucosal blood flow and suppression of neutrophil activation.

Administration, Oral↗
PubMed2003

Effect of repeated caffeine ingestion on repeated exhaustive exercise endurance.

PURPOSE: The purpose of this study was to examine the effect of repeated doses of caffeine on repeated exercise endurance. METHODS Nine male caffeine users performed exercise rides (ER) to exhaustion at 80% VO(2max) after ingesting a placebo, 5 mg x kg-1 of caffeine, or 2.5 mg x kg-1 of caffeine 1 h before the ER. Two ER were performed weekly on the same day once in the morning (AM) and 5 h later in the afternoon (PM). There were four treatments containing either caffeine or placebo, i.e., trial A representing 5-mg x kg-1 caffeine in the AM and 2.5-mg x kg-1 caffeine in the PM; trial B, which was placebo in both AM and PM; trial C representing 5-mg x kg-1 caffeine in the AM and placebo in the PM; and trial D representing a placebo in the AM and 5-mg x kg-1 caffeine in the PM. The order of the treatment trials was double blind and randomized. RESULTS: Caffeine ingestion significantly increased exercise time to exhaustion in the AM (trial A 24.9 +/- 10.2 min and trial C 21.8 +/- 4.9 vs trial B 18.0 +/- 6.4 min and D 17.7 +/- 4.3 min). This effect was maintained in the PM and greater than placebo (B 18.3 +/- 4.8 min) regardless of whether redosing (trial A 21.5 +/- 8.6 min) or placebo (trial C 21.0 +/- 6.8) followed the initial morning dose. Caffeine dosing in the PM (trial D 22.4 +/- 7.2 min) also increased ER after placebo trial D in the AM. CONCLUSIONS: It was concluded that redosing with caffeine after exhaustive exercise in the AM was not necessary to maintain the ergogenic effect of the drug during subsequent exercise 6 h later.

Administration, Oral↗
PubMed2003

Caffeine in fertilization medium is not essential for bovine IVF by fully capacitated spermatozoa.

The purpose of this study was to examine: 1) whether caffeine in the fertilization medium under mineral oil is essential for bovine in vitro fertilization by fully capacitated spermatozoa, 2) the minimum concentration of caffeine that shows an adverse effect on the motility of preincubated spermatozoa. Cumulus-oocyte complexes with heterogeneous-appearing ooplasm were matured in in vitro culture for 24 h and used for insemination. The fertilization rates of the preincubated spermatozoa introduced into the fertilization medium containing 0 mM or 5 mM caffeine were examined. The fertilization rate of the spermatozoa introduced into the medium without caffeine (final concentration of caffeine at fertilization was 0.27-0.35 mM) was significantly higher than that in the medium with 5 mM caffeine (82.4% vs 55.2%, P<0.05). When the final concentration of caffeine at fertilization was reduced ten-fold (0.02-0.03 mM), the fertilization rate was not significantly improved (86.0%). The motility of the preincubated spermatozoa introduced into the fertilization medium containing 0-5 mM caffeine was examined. The sperm motility in the fertilization medium without caffeine was significantly higher than that in the fertilization medium with more than 2 mM caffeine. These results indicate that caffeine in the fertilization medium is not essential for bovine in vitro fertilization by fully capacitated spermatozoa, and that more than 2 mM caffeine has an adverse effect on preincubated (capacitated) sperm motility.

Animals↗
PubMed1985

The effect of caffeine on cardiac rate, rhythm, and ventricular repolarization. Analysis of 18 normal subjects and 18 patients with primary ventricular dysrhythmia.

To determine clinical electrophysiologic effects of a moderate dose of caffeine, we compared prevailing cardiac rhythm and rate, the prevalence and frequency of ventricular dysrhythmia, and Q-T intervals in two populations over an initial 24-hour caffeine-free period and a subsequent 24-hour period in which caffeine was ingested in a dosage of 1 mg/kg of body weight at intervals of one half-life during waking hours. Group 1 was composed of 18 clinically normal subjects; group 2 was 18 subjects with frequent ventricular ectopic beats (VEBs) and no (n = 16) or minor (n = 2) cardiac disease. Sinus rhythm was the prevailing rhythm in all subjects at all times. For group 1, the mean sinus rate during the caffeine-free period was 77 +/- 10 beats per minute, compared to 73 +/- 9 beats per minute during the period of caffeine ingestion (not significant). Similarly, for group 2, the average sinus rate during the caffeine-free period was 76 +/- 11 beats per minute, not significantly different from the average sinus rate during the test period, 76 +/- 10 beats per minute. During abstention from caffeine, four of 18 subjects in group 1 had infrequent (less than 1/hr) VEBs, compared to nine of 18 during caffeine ingestion (not significant). In group 2, some 16 of the 18 subjects had VEBs during the caffeine-free period, with the frequencies varying from less than one VEB per hour to 1,449 VEBs per hour. During the test period, 14 of the 18 subjects in group 2 increased their VEB frequency, and the group's mean frequency rose from 207 +/- 350 VEBs per hour (control period) to 307 +/- 414 VEBs per hour (test period) (p less than 0.01). The Q-T interval in group 1, measured as the corrected Q-T interval (Q-Tc), averaged 0.430 +/- 0.027 during the caffeine-free period, not significantly different from the test period (0.425 +/- 0.019). The comparable Q-Tc values for group 2 were 0.424 +/- 0.018 during the caffeine-free period and 0.433 +/- 0.025 for the period of caffeine ingestion (not significant).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2001

A benefit-risk assessment of caffeine as an analgesic adjuvant.

Caffeine has been an additive in analgesics for many years. However, the analgesic adjuvant effects of caffeine have not been seriously investigated since a pooled analysis conducted in 1984 showed that caffeine reduces the amount of paracetamol (acetaminophen) necessary for the same effect by approximately 40%. In vitro and in vivo pharmacological research has provided some evidence that caffeine can have anti-nociceptive actions through blockade of adenosine receptors, inhibition of cyclo-oxygenase-2 enzyme synthesis, or by changes in emotion state. Nevertheless, these actions are only considered in some cases. It is suggested that the actual doses of analgesics and caffeine used can influence the analgesic adjuvant effects of caffeine, and doses that are either too low or too high lead to no analgesic enhancement. Clinical trials suggest that caffeine in doses of more than 65 mg may be useful for enhancement of analgesia. However, except for in headache pain, the benefits are equivocal. While adding caffeine to analgesics increases the number of patients who become free from headache [rate ratio = 1.36, 95% confidence interval (CI) 1.17 to 1.58], it also leads to more patients with nervousness and dizziness (relative risk = 1.60, 95% CI 1.26 to 2.03). It is suggested that long-term use or overuse of analgesic medications is associated with rebound headache. However, there is no robust evidence that headache after use or withdrawal of caffeine-containing analgesics is more frequent than after other analgesics. Case-control studies have shown that caffeine-containing analgesics are associated with analgesic nephropathy (odds ratio = 4.9, 95% CI 2.3 to 10.3). However, no specific contribution of caffeine to analgesic nephropathy can be identified from these studies. Whether caffeine produces nephrotoxicity on its own, or increases nephrotoxicity due to analgesics, is yet to be established.

Adjuvants, Pharmaceutic↗
PubMed2004

Caffeine synthase and related methyltransferases in plants.

Caffeine (1,3,7-trimethylxanthine) is a purine alkaloid present in high concentrations in tea and coffee and it is also found in a number of beverages such as coca cola. It is necessary to elucidate the caffeine biosynthetic pathway and to clone the genes related to the production of caffeine not only to determine the metabolism of the purine alkaloid but also to control the content of caffeine in tea and coffee. The available data support the operation of a xanthosine-->7-methylxanthosine-->7-methylxanthine-->theobromine-->caffeine pathway as the major route to caffeine. Since the caffeine biosynthetic pathway contains three S-adenosyl-L-methionine (SAM) dependent methylation steps, N-methyltransferases play important roles. This review focuses on the enzymes and genes involved in the methylation of purine ring. Caffeine synthase, the SAM-dependent methyltransferase involved in the last two steps of caffeine biosynthesis, was originally purified from young tea leaves (Camellia sinensis). The isolated cDNA, termed TCS1, consists of 1,483 base pairs and encodes a protein of 369 amino acids. Subsequently, the homologous genes that encode caffeine biosynthetic enzymes from coffee (Coffea arabica) were isolated. The recombinant proteins are classified into the three types on the basis of their substrate specificity i.e. 7-methylxanthosine synthase, theobromine synthase and caffeine synthase. The predicted amino acid sequences of caffeine biosynthetic enzymes derived from C. arabica exhibit more than 80% homology with those of the clones and but show only 40% homology with TCS1 derived from C. sinensis. In addition, they share 40% homology with the amino acid sequences of salicylic carboxyl methyltransferase, benzoic acid carboxyl methyltransferase and jasmonic acid carboxyl methyltransferase which belong to a family of motif B' methyltransferases which are novel plant methyltransferases with motif B' instead of motif B as the conserved region.

Amino Acid Sequence↗
PubMed2002

Single-dose bright light and/or caffeine effect on nocturnal performance.

BACKGROUND: The impact of the separate and combined effects of a 1-h exposure to bright light (approximately 3000 lx) and a 200-mg dose of caffeine on nocturnal performance was studied during a simulated shift-work schedule beginning 1730 in the evening and ending 1000 the next morning. HYPOTHESIS: Light and caffeine exposure were expected to improve nocturnal fatigue degradation. METHODS: There were 11 subjects tested under 4 treatment conditions: 1) 1 h Dim Light-Placebo; 2) 1 h Bright Light-Placebo; 3) 1 h Dim Light-Caffeine; 4) 1 h Bright Light-Caffeine. Exposure to the light occurred between 0130 and 0230 hours. Caffeine or placebo was administered at 0140 hours. RESULTS: Choice Reaction Time (RT) recorded during the four post-treatment sessions were shorter for the Bright Light-Caffeine, Bright Light-Placebo, and Dim Light-Caffeine conditions than for the Dim Light-Placebo condition. During the sessions beginning 0430 and 0830 hours, the shortest RT was recorded for the Bright Light-Caffeine treatment. The largest number of trials without false alarms per session for the working memory task (letter cancellation) was found for the Bright Light-Caffeine condition. Exposure for 1 h to 3000 lx reduced melatonin concentration between 42-47% from 0230 to 0410 hours. A 200-mg dose of caffeine also reduced melatonin levels, although to a lesser degree than 1 h exposure to 3000 lx. CONCLUSION: Although 1 h exposure to bright light at 0130 hours combined with a 200-mg dose of caffeine maintains performance throughout the remainder of the night/early morning, a 1-h exposure to bright light without the caffeine may actually degrade performance.

Adult↗
PubMedDate not supplied

Urinary recovery of caffeine and its metabolites in healthy African children.

Consumption of caffeine containing products is very popular in African children, particularly during ill health in the belief that caffeine promotes good health. This study aims to define the metabolism of caffeine, which takes place in the liver in a group of healthy Nigerian children. About 100 mg of caffeine was ingested after an overnight fast. Urine was collected before caffeine ingestion and over 12-hour periods for 36 hours in 13 healthy Nigerian children. The percentage of caffeine and metabolites recovered in urine was determined by high performance liquid chromatography. The total urinary caffeine and metabolites recovered over the 36-hour sampling period was 63.6%, with only 0.4% of the caffeine dose ingested recovered as unchanged caffeine during the same period. Insignificant amounts of 3,7-dimethyluric acid (0.2%), 3-methyluric acid (0.3%) and 1,3,7-dimethyluric acid (0.4) were recovered in the 36hour urine sample. This study also found that the N3-demethylation pathway was the principal pathway of caffeine metabolism accounting for 83.3% of the total metabolites recovered while C8-hydroxylation accounted for only 0.6% of metabolites recovered. The pattern of urinary metabolites recovered suggested that N3-demethylation is the principal pathway of caffeine metabolism in healthy African children and that small amounts of unchanged caffeine, as well as 3,7-dimethyluric acid, 3-methyluric acid and 1,3,7-dimethyluric acid were recovered during the sampling period.

Administration, Oral↗
PubMedDate not supplied

Effects of classic and newer antidepressants on the oxidation pathways of caffeine in rat liver. In vitro study.

Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtazapine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated antidepressants, with an exception of mirtazapine, added in vitro to liver microsomes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic pathways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 microM, respectively), the effect on 1-N- and 7-N-demethylation being the most pronounced. Clomipramine showed distinct inibition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, 45.6 microM, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 microM). Sertraline decreased significantly the rate of 1-N- and 3-N-demethylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 microM, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 microM). Nefazodone displayed clear effect on 3-N- and 7-N-demethylation (Ki = 68.8 and 66.4 microM, respectively), but was weak in inhibiting 1-N-demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 microM, respectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hydroxylation (Ki = 264 and 455 microM, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested antidepressants (with an exception of mirtazapine) may lead to drug-drug metabolic interactions at a level of a few CYP isoforms. The obtained results provide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine.

Animals↗
PubMedDate not supplied

Influence of classic and atypical neuroleptics on caffeine oxidation in rat liver microsomes.

Caffeine is a marker drug for testing the activity of CYP1A2 (3-N-demethylation) in humans and rats. Moreover, CYP3A seems to be essential for its metabolism (8-hydroxylation). In the case of 1-N- and, in particular, 7-N-demethylation of caffeine, apart from CYP1A2, other CYP isoenzymes play a considerable role, probably CYP2B and/or CYP2E1. The aim of the present study was to investigate the influence of two classic neuroleptics (promazine and haloperidol) and two atypical ones (risperidone and sertindole) on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that promazine, a phenothiazine neuroleptic with the simplest chemical structure, significantly inhibited 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine via competitive or mixed mechanism (Ki = 21.8, 25.4 and 58.2 microM, respectively). This indicates inhibition by promazine of CYP1A2 (inhibition of 3-N- and 1-N-demethylation), and possibly CYP3A2 (inhibition of 8-hydroxylation), but not of other CYP isoenzymes involved in 7-N-demethylation of caffeine (e.g. CYP2B2 and/or CYP2E1). In contrast to promazine, haloperidol had no effect on the oxidation reactions of caffeine in the applied in vitro metabolic model. The potency of inhibition of caffeine oxidation by risperidone and sertindole resembled rather haloperidol than promazine. Risperidone appeared to be a very weak inhibitor of 3-N-demethylation and 8-hydroxylation (Ki = 202.5 microM) and had no effect on 1-N- and 7-N-demethylation of caffeine. Sertindole was a very poor inhibitor of 1-N- and 7-N-demethylations and 8-hydroxylation pathways of the marker substance (Ki = 132.1, 434.1 and 173.3 microM, respectively); even the observed in vitro inhibition of 3-N-demethylation of caffeine by sertindole (Ki = 68.9 microM) cannot be of practical significance in vivo, considering extremely low pharmacological and therapeutic doses of the neuroleptic. In summary, among the investigated neuroleptics, only promazine showed significant inhibitory activity towards caffeine metabolism in vitro (inhibition of CYP1A2 and possibly CYP3A), which may be of pharmacological and clinical importance in vivo. In contrast to promazine, haloperidol and the investigated atypical neuroleptics had no or very weak effect on caffeine oxidation in vitro,of no in vivo significance. Considering the results of the present and previous studies, it seems highly likely that promazine may cause pharmacokinetic interactions, while atypical neuroleptics seem to be safe in this respect. Moreover, the observed reaction-dependent effects of promazine and sertindole provide indirect evidence that CYP1A2 is not the only isoenzyme important for the metabolism of caffeine, which requires further pharmacological and clinical consideration.

Animals↗
PubMedDate not supplied

Anti-obesity effects of three major components of green tea, catechins, caffeine and theanine, in mice.

To elucidate the anti-obesity effects of three major components of green tea, catechins, caffeine and theanine, female ICR mice were fed on diets containing 2% green tea powder and diets containing 0.3% catechins, 0.05% caffeine and 0.03% theanine, which correspond, respectively, to their concentrations in a 2% green tea powder diet, singly and in combination for 16 weeks. Body weight and food intake were determined monthly during this period, kidneys, adrenals, liver, spleen, brain, pituitary and intraperitoneal adipose tissues (IPAT) were weighed and lipid levels in the serum and liver were measured at the end of this period. The body weight increase and weight of IPAT were significantly reduced by the diets containing green tea, caffeine, theanine, caffeine + catechins, caffeine + theanine and caffeine + catechins + theanine. Noticeably, the IPAT weight decreased by 76.8% in the caffeine + catechins compared to the control group. Serum concentrations of triglycerides (TG) and non-esterified fatty acids (NEFA) were decreased by green tea, catechins and theanine. Moreover, caffeine + catechins, caffeine + theanine and caffeine + catechins + theanine also decreased NEFA in the serum. The TG level in the liver was significantly reduced by catechins and catechins + theanine in comparison with the control. These results indicated that at least caffeine and theanine were responsible for the suppressive effect of green tea powder (GTP) on body weight increase and fat accumulation. Moreover, it was shown that catechins and caffeine were synergistic in anti-obesity activities.

Adipose Tissue↗