Caffeine clearance and biotransformation in patients with chronic liver disease

1. The clearance and biotransformation of caffeine (1,3,7-trimethylxanthine) were investigated in eight healthy control subjects and 16 patients with cirrhosis, by measuring serial serum caffeine concentrations and recoveries of methylxanthine metabolites in urine for 48 h after a 400 mg oral caffeine load. 2. In the control group, the mean (+/- SD) serum caffeine clearance was 1.3 +/- 0.4 ml min-1 kg-1 and a mean of 56.4 +/- 16.5% of the administered caffeine was recovered from the urine over 48 h as methyluric acids and methylxanthines. The majority of the metabolites were excreted in the first 24 h period and only 2.0 +/- 1.4% of the administered caffeine was excreted unchanged. 3. Patients with compensated cirrhosis (n = 10) metabolized caffeine similarly to the control subjects. Thus the mean serum caffeine clearance was 1.4 +/- 1.2 ml min-1 kg-1 and a mean of 57.2 +/- 11.7% of the administered caffeine was recovered from the urine over 48 h. The majority of the metabolites were excreted in the first 24 h; the pattern of metabolic excretion was unaltered and only 2.2 +/- 0.9% of the administered caffeine was excreted unchanged. 4. In the patients with decompensated cirrhosis (n = 6), significant changes were observed in caffeine metabolism. The mean serum caffeine clearance (0.4 +/- 0.2 ml min-1 kg-1) was significantly impaired compared with controls (P less than 0.01) and a significant delay was observed in metabolite excretion in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure.

Phenytoin (DPH) and its two major metabolites, conjugated and unconjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-OH-DPH), have been studied in plasma and urine to 4 healthy subjects and 3 uremic patients during two weeks on DPH, 0.1 gm daily. Only 0.4% to 1.2% of the dose was excreted as unchanged DPH. The DPH concentrations in urine were in the same range as calculated unbound levels of DPH in plasma in the normal subjects; 1% to 2% of the dose was excreted as unconjugated 4-OH-DPH in the normal subjects. In the uremic patients, renal clearance of this metabolite was reduced to one-sixth that percentage. Plasma concentrations rose to values twice as high as normal, indicating increased rate of glucuronidation. Urinary recovery of conjugated 4-OH-DPH in healthy subjects was 52% to 94%. Its renal clearance was close to glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration only. Plasma concentrations of conjugated 4-OH-DPH reached plateau levels around day 4 in normal subjects. In the uremic patients, plasma concentrations of this metabolite accumulated to levels 10 times normal, and after 15 days of medication plateau levels did not seem to have been reached.     

Studies on the tryptophan load test in man

Summary Studies on the tryptophan load test were carried out by measuring the urinary excretion of 10 tryptophan metabolites via the kynurenine pathway in 25 healthy men and 20 women after oral L-tryptophan loading with dosages of 2 g, 50 mg/kg or 75mg/kg body weight. With increasing doses of the amino acid, a difference was found between the male and female groups in the pattern of excretion of the tryptophan metabolites. In both groups, kynurenine and kynurenic acid were the metabolites excreted in the greatest amounts. The results indicate that the most useful loading dose of L-tryptophan for both men and women is 50 mg/kg body weight, as with 2 g L-tryptophan the excretion of the metabolites is too low and varies too much between the two groups of male and female subjects. On the other hand, the load with 75 mg/kg body weight can cause an overloading, particularly in women. No significant variations in the levels of the metabolites were found in the urine of two female subjects at different stages of the menstrual cycle after loading doses of 2 g and 50 mg/kg body weight. On the basis of the determination of the serum tryptophan levels, the period of urine collection was established as 10 h.     

Liquid chromatographic assay for metronidazole and tinidazole: pharmacokinetic and metabolic studies in human subjects.

We developed methods for measuring metronidazole, its two major metabolites, and tinidazole in serum and urine. After treatment of each sample with an equal volume of 5% perchloric acid, the drugs were separated by reverse-phase high-pressure liquid chromatography (retention times, 6 to 18 min). Quantitation was based on spectrometry at 320 nm. These assays were sensitive, rapid, and specific, and recoveries from biological samples were quantitative. Metronidazole and tinidazole were given as rapid intravenous infusions to four healthy human volunteers. The biological half-lives of these two compounds were 5.4 and 11.1 h, respectively. The hydroxy metabolite of metronidazole appeared quickly in serum and was eliminated at a slow rate. The acetic acid metabolite of metronidazole was detected in serum at very low levels and only for a limited time. No metabolic products of tinidazole were found in serum samples. In urine, 43.7% of the administered dose of metronidazole was recovered over a period of 24 h (24.1% of the dose as the hydroxy metabolite, 12.0% as the acetic acid metabolite, and 7.6% as unchanged drug). Only 18.4% of the infused dose of tinidazole was eliminated in urine over a period of 72 h, and no metabolic products were detected.     

Disposition of [14C]aztreonam in rats, dogs, and monkeys

[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.     

Arsenic metabolites in human urine after ingestion of an arsenosugar.

BACKGROUND: Arsenic-containing carbohydrates (arsenosugars) are common constituents of marine algae, including those species used as human food. The toxicology of these compounds has not been fully evaluated. METHODS: Arsenic metabolites in human urine were monitored over a 4-day period after ingestion of a synthetic specimen of arsenosugar. The metabolites were determined by HPLC-inductively coupled plasma mass spectrometry, and structural assignments were confirmed with liquid chromatography-electrospray ionization mass spectrometry. RESULTS: Approximately 80% of the total ingested arsenic was excreted in the urine during the 4 days of the experiment. There was a lag-period of approximately 13 h before substantial quantities of arsenic appeared in the urine, and the excretion rate peaked between 22 and 31 h. At least 12 arsenic metabolites were detected, only 3 of which could be positively identified. Dimethylarsinate (DMA) was the major metabolite, constituting 67% of the total arsenicals excreted. A new urinary arsenic metabolite, dimethylarsinoylethanol, represented 5% of the total arsenicals, whereas trimethylarsine oxide was present as a trace (0.5%) constituent. One other significant metabolite cochromatographed with a reduced DMA standard, and hence was possibly dimethylarsinous acid. The second most abundant metabolite in the urine (20% of the total arsenic) remained unidentified, whereas the rest of the excreted arsenic was made up of several trace metabolites and small amounts of unchanged arsenosugar. CONCLUSIONS: Arsenosugars are biotransformed by humans to at least 12 arsenic metabolites, the toxicologies of which are currently unknown.     

Serum and Urinary Concentrations of Cyclacillin in Humans

Cyclacillin is a semisynthetic penicillin produced from the penicillin nucleus (6-aminopenicillanic acid) by acylation with 1-aminohexanecarboxylic acid. The absorption and excretion characteristics of cyclacillin were defined in one completely randomized and three three-way crossover experiments. Mean peak serum cyclacillin levels appeared earlier and were fivefold higher than those obtained with equal doses of ampicillin. High serum cyclacillin concentrations were reached at 0.5 h and by 2 h were lower than ampicillin. Serum ampicillin concentrations peaked at 1.5 h, remaining slightly higher than those for cyclacillin for the next 4.5 h. The mean area for the cyclacillin curve was significantly superior to either of the ampicillin formulations. Mean serum concentrations of cyclacillin exhibited a smooth dose-response, approximately doubling in each instance as the dose was doubled from 250 to 500 and from 500 to 1,000 mg. High concentrations of cyclacillin were also demonstrated in urine. Neither ratio of drug to metabolite in the urine nor the percent of excretion was significantly affected by the dose level. Sixty-seven percent of the drug was excreted unchanged, and 17% was excreted as penicilloic acid, with most of the excretion occurring within 6 h of administration. In subjects given 500 mg of cyclacillin (four times daily) for 6 days, 2% of the drug was excreted as 1-aminocyclohexanecarboxylic acid, and approximately 55% (24 to 91%) was unchanged. Neither formation nor excretion of the former was sex dependent.     

Encainide disposition in patients with renal failure

The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form O-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhythmic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t1/2 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites.     

Determination of apalcillin and its metabolites in human body fluids by high-pressure liquid chromatography.

We describe two methods for the quantitative analysis of apalcillin and its metabolites in serum and urine by reverse-phase high-pressure liquid chromatography (HPLC), a fast isocratic method for the parent drug, and a gradient method that allows the simultaneous assay of two metabolites. Serum was deproteinized with acetonitrile, and urine was diluted with buffer solution. The detection limit was about 0.5 micrograms/ml at a detection wavelength of 254 nm and 1.5 micrograms/ml at 310 nm. Within-batch precision (coefficient of variation) varied from 10.2 to 1.1% for concentrations of 7.8 and 185.3 micrograms/ml of serum, respectively. Recovery rates of 95.1 and 97.7% were found in spiked sera. Results obtained by HPLC correlated well with those from a standard microbiological assay (agar diffusion test); the resulting bivariate regression equation for serum was y-bioassay = 2.5 micrograms/ml + 0.992 X xHPLC, and that for urine was ybioassay = 12.0 micrograms/ml + 1.009 X xHPLC. At a detection wavelength of 315 nm, no interferences were observed in 10 healthy volunteers. Healthy subjects who were given 2 g of apalcillin intravenously excreted 18% of the parent drug within 24 h in the urine. Two inactive compounds were furthermore identified in urine as the isomeric forms of the penicilloic acids. Their excretion within 24 h amounted to 6.9 and 11.2% of the dose.     

Review of single- and multiple-dose pharmacokinetics of the monobactam, aztreonam (SQ 26,776) in healthy subjects

Aztreonam (SQ 26,776) is a new, completely synthetic, monocyclic beta-lactam antibiotic with potent activity against most aerobic gram-negative bacteria. The pharmacokinetics of single intravenous doses of 125-4,000 mg, single intramuscular doses of 250-1,000 mg, and multiple intravenous and intramuscular doses of 500 and 1,000 mg q.8 h during 7 days, were studied in 90 healthy male subjects. The half-life was 1.7, apparent volume of distribution 0.2 liters/kg, serum protein binding 56%, and urinary excretion 60-70% of the dose. No significant accumulation or change in pharmacokinetics of aztreonam was found during q.8 h dosing. Small amounts of the biologically inactive open beta-lactam ring metabolite, SQ 26,992, were found in the urine. Aztreonam level in serum and urine after 500- to 2,000-mg doses were potentially therapeutic for most Enterobacteriaceae and Pseudomonas aeruginosa.     

In vivo catabolism of histamine in the human stomach

The importance of the stomach in the magnitude of excreted amounts of the major histamine metabolite in the urine was studied during total parenteral nutrition in five patients before and after total gastrectomy. In all subjects, a reduction in the 24-h urinary excretion of methylimidazoleacetic acid was observed. No corresponding effect was seen after an operation because of abdominal aortic aneurysm. In patients with duodenal ulcer disease and those submitted to a cholecystectomy because of cholecystolithiasis, we studied the catabolism of histamine in the stomach by injecting 14C-histamine directly into the portal vein and, simultaneously, 3H-histamine intra-arterially to the corpus fundus region of the stomach and subsequently determining the urinary excretion of 14C. 3H-histamine and their basic and acid metabolites, respectively. We found no apparent difference in the pattern of excreted 14C and 3H metabolites between the two patients groups, indicating that the catabolism of histamine in the stomach of patients with duodenal ulcer disease is similar to that in 'healthy' controls.     

Disposition of caffeine and its metabolites in man

The disposition of caffeine and its metabolites was studied in six healthy subjects by use of sensitive and specific assays. The primary degradation of caffeine in man was found to be N-demethylation and/or ring oxidation to theophylline, paraxanthine, theobromine and 1,3,7-trimethyluric acid. These compounds were further degraded to dimethylated uric acids, monomethylxanthines and monomethyluric acids. About 3 and 6% of the drug was converted to theophylline and theobromine, respectively. The elimination of paraxanthine after its formation did not follow linear kinetics. A large urine recovery of 1-methylxanthine after caffeine administration in comparison with the amount recovered after administration of theophylline suggests an inhibitory effect on the degradation of this metabolite by either caffeine itself or another metabolite of caffeine. Caffeine and its primary metabolites, dimethylxanthines, were extensively reabsorbed in the renal tubule. Their renal clearances were highly urine flow-dependent and their urinary excretion varied with urine output during the study. About 70% of the dose was recovered in the urine. Postulated degradation pathways of caffeine are discussed.     

Congenital adrenal hyperplasia. Plasma and urinary steroid conjugates in seven children with steroid 21-hydroxylase deficiency

Plasma neutral steroid sulphates and urinary neutral steroid sulphates and glucuronides from seven children (0.17–10.4 years) with steroid 21-hydroxylase deficiency were determined using gas-liquid chromatography and gas chromatography -mass spectrometry. Three of the patients were salt-losers. Large inter-individual variation in plasma concentration and urinary excretion of these compounds was observed. However, the group did have certain characteristic features. In plasma, the main compounds present were 3β-hydroxy-5-ene steroids. A progesterone metabolite, 5α-pregnane-3β,20α-diol, and a 17α-hydroxyprogesterone metabolite, 5β-pregnane-3α, 17α, 20α-triol, were present as sulphate conjugates and 3α, 17α-dihydroxy-5β-pregnan-20-one sulphate was identified for the first time in human peripheral plasma. In the urine, metabolites of 17α-hydroxyprogesterone were predominant and 5β-pregnane-3α, 17α,20α-triol, excreted mainly as a glucuronide, alone comprised about 50% of the neutral steroid excretion in these subjects. The next most abundant steroid was 3α,17α,20α-trihydroxy-5β-pregnan-11-one. The following compounds have not previously been found in the urine of patients with steroid 21-hydroxylase deficiency but were found in the present subjects: 5-androstene-3β, 17β-diol, 5α-pregnane-3β, 20α-diol and 3β,17α-dihydroxy-5β-pregnan-20-one. The pattern of the plasma and urinary steroids determined clearly differentiates the subjects with a steroid 21-hydroxylase defect from normal subjects and from patients with a 3β-hydroxysteroid dehydrogenase deficiency.     

Metabolism of Vitamin D3-3H in Human Subjects: Distribution in Blood, Bile, Feces, and Urine

Vitamin D(3)-(3)H has been administered intravenously to seven normal subjects, three patients with biliary fistulas, and four patients with cirrhosis. Plasma D(3)-(3)H half-times normally ranged from 20 to 30 hours. in vivo evidence that a metabolic transformation of vitamin D occurs was obtained, and a polar biologically active vitamin D metabolite was isolated from plasma.Urinary radioactivity averaged 2.4% of the administered dose for the 48-hour period after infusion, and all the excreted radioactivity represented chemically altered metabolites of vitamin D. The metabolites in urine were mainly water-soluble, with 26% in conjugated form.From 3 to 6% of the injected radioactivity was excreted in the bile of subjects with T-tube drainage and 5% in the feces of patients having no T-tube. The pattern of fecal and biliary radioactivity suggested that the passage of vitamin D and its metabolites from bile into the intestine represents an essential stage for the fecal excretion of vitamin D metabolites in man.Abnormally slow plasma disappearance of vitamin D(3)-(3)H in patients with cirrhosis was associated with a significant decrease in the quantity and rate of glucuronide metabolite excretion in the urine.     

Kinetics and dynamics of quinidine-N-oxide in healthy subjects

The pharmacokinetics of a major metabolite of quinidine in humans, quinidine-N-oxide, were investigated after single oral doses (3 to 15 mg) in four healthy subjects. The concentration in serum and urine was determined by an HPLC assay. Because of a small volume of distribution, the elimination half-life of quinidine-N-oxide was only 2.5 +/- 0.28 hours (mean +/- SD), considerably shorter than that of quinidine. The renal clearance was 1.3 +/- 0.3 L/hr. Only 13.9% +/- 3.7% of the dose was recovered in urine as unchanged compound for up to 12 hours. Two unidentified compounds with the same retention time as quinidine and 3-hydroxyquinidine were found in the urine samples of two subjects. The free fraction in serum was 3.3% +/- 0.83%. No systematic changes in heart rate-corrected QT interval were observed up to concentrations of 500 ng/ml. The results indicate that quinidine-N-oxide, in contrast to 3-hydroxyquinidine, does not possess quinidine-like pharmacologic activity.     

Pharmacokinetics of Bay k 4999, a New Broad-Spectrum Penicillin

The pharmacokinetics of the broad-spectrum penicillin Bay k 4999 were studied in six healthy male volunteers. A 2-g dose was given by the intravenous route. The tissue penetration of the antibiotic was studied by both dermabrasion and blister techniques. A total of 26.4% of the drug was recovered in the urine in 24 h, 79% of this being excreted in the first 2 h. The elimination half-life in serum was 1.3 h. The dermabrasion levels of Bay k 4999 were generally similar to those in serum, but after 1 h the blister fluid levels of antibiotic were greater than those in serum. Different drug levels obtained by blister and dermabrasion techniques may be due to the different composition of the two fluids.     

Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man

Conjugates of 3-methylthio-4-hydroxyactanilide were found in the urine of dogs and humans treated with phenacetin (4-ethoxyacetanilide) or acetaminophen (4-hydroxyacetanilide). About 1% to 3% of the administered dose was excreted as this thiomethyl metabolite after administration of phenacetin or acetaminophen to dogs. An average of 0.39% of the dose was excreted in the urine as 3-methylthio-4-hydroxyacetanilide conjugates after administration of phenacetin to several subjects, and an average of 0.66% of the dose was excreted as this metabolite in the urine after administration of acetaminophen to humans. The possibility that the thiomethyl metabolite is derived from a mercapturic acid conjugate or an N-hydroxy derivative of phenacetin or acetaminophen is discussed.     

Metabolic response of humans to ingestion of nicotinic acid and nicotinamide.

The identification of nicotinamide-N1-oxide as a metabolite in the urine of a schizophrenic patient prompted a study of the relative metabolism of nicotinic acid and nicotinamide in mental patients and healthy volunteers. Metabolites quantified included N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide, N1-methylnicotinamide, nicotinuric acid, and nicotinamide-N1-oxide. More of most of these metabolites evidently was excreted after nicotinamide ingestion than after nicotinic acid. At the highest doses (3000 mg/day), the relative proportions of these metabolites in the urine were changed. There were only slight difference between healthy individuals and mental patients in the quantities of metabolites excreted, and no statistically significant trends were noted.     

Amoxicillin: In Vitro and Pharmacological Studies

Amoxicillin is a new semisynthetic penicillin which is active in vitro against gram-positive cocci (except penicillin G-resistant Staphylococcus aureus) and most isolates of Proteus mirabilis and Escherichia coli. Its in vitro activity is quite similar to ampicillin, but it produces higher serum levels after oral administration. The mean peak serum levels of amoxicillin in 11 normal volunteers were 2.30 mug/ml after 125 mg, 3.43 mug/ml after 250 mg, 6.75 mug/ml after 500 mg, and 9.90 mug/ml after 1 g. About 70% of the drug was excreted in the urine during the first 6 hr.     

In vivo catabolism of histamine in the human stomach

The importance of the stomach in the magnitude of excreted amounts of the major histamine metabolite in the urine was studied during total parenteral nutrition in five patients before and after total gastrectomy. In all subjects, a reduction in the 24-h urinary excretion of methylimidazoleacetic acid was observed. No corresponding effect was seen after an operation because of abdominal aortic aneurysm. In patients with duodenal ulcer disease and those submitted to a cholecystectomy because of cholecystolithiasis, we studied the catabolism of histamine in the stomach by injecting ¹⁴C-histamine directly into the portal vein and, simultaneously, ³H-histamine intra-arterially to the corpus fundus region of the stomach and subsequently determining the urinary excretion of ¹⁴C, ³H-histamine and their basic and acid metabolites, respectively. We found no apparent difference in the pattern of excreted ¹⁴C and ³H metabolites between the two patients groups, indicating that the catabolism of histamine in the stomach of patients with duodenal ulcer disease is similar to that in ‘healthy’ controls.