Grapefruit juice and kidney stones.
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Beverages↗
Biomedical subjects
B Ameer
Publications and source records attributed to B Ameer.
Drug interactions with grapefruit juice.
Some drugs demonstrate a significantly greater (up to 3-fold) mean oral bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompanied by altered drug action. Study design factors possibly contribute to the magnitude of changes in drug bioavailability; they include the source of the citrus, its intake schedule, drug formulations and individual metabolising capacity. The components of citrus juice that are responsible for clinical drug interactions have yet to be fully determined. Based on the flavonoid naringin's unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enzymes, naringin is likely to be one of the grapefruit components influencing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interaction studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably the inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3A substrates support the mechanistic hypothesis that 1 or more grapefruit juice components inhibit CYP3A enzymes in the gastrointestinal tract. The evaluation of the need to avoid the concomitant intake of grapefruit products with drugs is best done on an individual drug basis rather than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recipients, its interaction with grapefruit juice is likely to be clinically significant.
Anti-Anxiety Agents↗
Flavanone absorption after naringin, hesperidin, and citrus administration.
Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once-daily grapefruit. Cumulative urinary recovery indicated low bioavailability ( < 25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma by positive chemical ionization-collisionally activated dissociation tandem mass spectrometry (PCI-CAD MS/MS). After juice administration, PCI-CAD MS/MS detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.
Adult↗
Outcomes research: exploring the unanticipated.
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Clinical Trials as Topic↗
Acetaminophen hepatotoxicity augmented by zidovudine.
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Acetaminophen↗
Kinetic and inhibitor studies of acetaminophen and zidovudine glucuronidation in rat liver microsomes.
The antiviral drug zidovudine (ZDV) and the analgesic and antipyretic agent acetaminophen (AP) are both biotransformed in the liver of humans to ether glucuronides. A previous clinical trial of ZDV suggested the potential for a clinically significant interaction between AP and ZDV, probably based upon competing hepatic metabolism. To study the mechanism of this potential competition between AP and ZDV as substrates for uridine diphosphoglucuronyltransferase (UDPGT), enzyme kinetic studies were performed using rat liver microsome preparations. Cross inhibition studies demonstrated that AP glucuronidation was competitively inhibited by ZDV, while ZDV glucuronidation was slightly inhibited by AP in a noncompetitive interaction.
Acetaminophen↗
Systemic absorption of topical lidocaine in elderly and young adults undergoing bronchoscopy.
This study compared the systemic absorption of topically administered lidocaine in elderly and young adult patients who were undergoing fiberoptic bronchoscopy. Fourteen elderly subjects aged 60-72 years (mean 67 years) and five young subjects age 31-48 years (mean 42 years) were compared with respect to dosage requirements to achieve satisfactory local anesthesia, rate and extent of lidocaine systemic absorption, plasma drug levels, elimination half-life, and drug side effects. Blood samples were drawn prior to, during, and for an average of 3 hours after the completion of bronchoscopy. Lidocaine plasma concentrations averaged in the range of 3.04-0.88 micrograms/ml from the beginning of the procedure to the end of blood sampling. Despite high cumulative amounts of 19 mg/kg (1200 mg) of lidocaine administered topically, the regimen proved relatively safe and achieved satisfactory anesthesia. In patients without known risk factors either for delayed hepatic lidocaine clearance or for enhanced mucosal absorption, the regimen is suitable for both young and old individuals.
Administration, Topical↗
Renal and hemodynamic responses to bumetanide in hypertension: effects of nitrendipine.
The effects of a calcium antagonist on the response to a loop diuretic were tested in eight hypertensive patients while they received 120 mmol.24 hr-1 of dietary Na. Nitrendipine (N; 20 mg) or placebo (P) was administered twice daily for five days and bumetanide (B; 1 mg, i.v.) for the last three days of each period. Cardiac index (CI) was measured during tilt. B alone significantly (P less than 0.05; N = 7) reduced CI and increased total peripheral resistance; N prevented these effects of B. Neither drug altered BP consistently. Although three days of B increased plasma renin activity (PRA) during P and N, it increased plasma aldosterone (PAldo) only during P (P, 4.4 +/- 1.3 to 7.6 +/- 1.0; P less than 0.05, N, 5.7 +/- 1.3 to 6.0 +/- 1.3; pg.liter-1; NS). B increased Na excretion without changing GFR or RPF; this was followed by 18 hours of decreased renal Na excretion. These actions were unchanged by N. N did not change the cumulative excretion of B (P, 268 +/- 35 vs. N, 217 +/- 21 micrograms) or the relationship between Na excretion and the log of B excretion. However, Na excretion was increased (P less than 0.05) by 40 to 60% in the six hour period following the first two doses of N. Therefore, the cumulative Na balance was more negative during five days of N (P, -47 +/- 17 vs. N, -108 +/- 24 mmol; P less than 0.05). The effect of N and B on Na balance were independent.(ABSTRACT TRUNCATED AT 250 WORDS)
Bumetanide↗
Rifampin-associated thrombocytopenia secondary to poor compliance.
Rifampin can be associated with severe adverse effects such as hepatitis, acute renal failure, hemolytic anemia, and thrombocytopenia. Thrombocytopenia has traditionally been associated with intermittent therapy. This article reports the occurrence of rifampin-associated thrombocytopenia in an indigent patient after a four-month lapse in therapy for pulmonary tuberculosis. The patient's platelet count dropped rapidly to a level of 1000/mm3 after receiving a single 600 mg dose of rifampin. After returning to a normal level of greater than 100,000/mm3, the patient's platelets again dropped to 1200/mm3 with readministration of rifampin. The long-term therapy necessary to eradicate the Mycobacterium tuberculosis organism makes economic considerations important. This patient and other indigent patients who may be poor compliers because they are unable to buy the necessary medication may be at a higher risk for adverse reactions.
Adult↗
Rapid mucosal absorption of topical lidocaine during bronchoscopy in the presence of oral candidiasis.
Local anesthetic agents are topically applied during diagnostic procedures such as bronchoscopy. These routine procedures are associated with only rare reports of drug toxicity or extensive systemic drug absorption. We report a case of rapid systemic absorption and elevated plasma lidocaine concentrations following a fiberoptic bronchoscopy procedure in a man with oral candidiasis and lung cancer.
Absorption↗
Selecting clindamycin dosage regimens.
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Clindamycin↗
Usefulness of oral dipyridamole suspension for stress thallium imaging without exercise in the detection of coronary artery disease.
Stress thallium imaging with intravenous dipyridamole permits assessment of coronary artery disease (CAD) without the need for exercise. However, intravenous dipyridamole is available in the United States only on an experimental basis. To study the use of oral dipyridamole as a clinically available alternative to intravenous dipyridamole for this purpose, 100 patients underwent thallium imaging with oral dipyridamole. Each patient received 300 mg of pulverized tablets in a 30-ml suspension. Maximal increase in mean heart rate and decrease in mean blood pressure occurred 30 minutes after ingestion. At 45 minutes, 2 mCi of thallium was given intravenously and serial imaging was begun within 7 minutes. The serum dipyridamole level (mean +/- standard deviation) 45 minutes after 300 mg was administered orally (3.7 +/- 2.2 micrograms/ml) was similar to that 5 minutes after 0.56 mg/kg was given intravenously (4.6 +/- 1.3 micrograms/ml). Fifty-five patients had some adverse effects between 15 and 75 minutes after oral ingestion, including nausea, headache, dizziness, chest pain (25 patients) and electrocardiographic changes (14 patients). Intravenous aminophylline was used to resolve these adverse effects in 21 patients. There were no severe arrhythmias, myocardial infarctions or deaths. Of the 43 patients with angiographically documented CAD, 39 had an initial perfusion defect that redistributed on the delayed images. When the results in patients who had undergone catheterization were analyzed by individual segment, the presence of thallium redistribution was associated with normal or hypokinetic contrast left ventriculographic wall motion of that segment, whereas the presence of a persistent defect was associated with akinesia or dyskinesia (Fisher's standardized Z = 9.14).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Paracetamol absorption from a feeding jejunostomy.
Disposition of paracetamol oral elixir was determined in two male patients after administration via feeding jejunostomy and compared with four male controls who received the same dose by mouth. Area under the plasma concentration-time curve, elimination half-life, and time to maximum concentration were similar in both groups after 650 mg paracetamol elixir. The absolute amounts and ratio of paracetamol glucuronide to sulphate, the major urinary metabolites after therapeutic paracetamol doses, were similar after jejunal administration as compared to oral administration. Paracetamol is absorbed and biotransformed in a similar manner after either jejunal or oral administration. Therefore, it may be administered effectively via jejunostomy tube in patients who require this route of administration.
Acetaminophen↗
Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation.
Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
Absolute and relative bioavailability of oral acetaminophen preparations.
Eighteen healthy volunteers received single 650-mg doses of acetaminophen by 5-min intravenous infusion, in tablet form by mouth in the fasting state, and in elixir form orally in the fasting state in a three-way crossover study. An additional eight subjects received two 325-mg tablets from two commercial vendors in a randomized crossover fashion. Concentrations of acetaminophen in multiple plasma samples collected during the 12-hr period after each dose were determined by high-performance liquid chromatography. Following a lag time averaging 3-4 min, absorption of oral acetaminophen was first order, with apparent absorption half-life values averaging 8.4 (elixir) and 11.4 (tablet) min. The mean time-to-peak concentration was significantly longer after tablet (0.75 hr) than after elixir (0.48 hr) administration. Peak plasma concentrations and elimination half-lives were similar following both preparations. Absolute systemic availability of the elixir (87%) was significantly greater than for the tablets (79%). Two commercially available tablet formulations did not differ significantly in peak plasma concentrations, time-to-peak, or total area under the plasma concentration curve and therefore were judged to be bioequivalent.
Acetaminophen↗
Differential effect of cimetidine on drug oxidation (antipyrine and diazepam) vs. conjugation (acetaminophen and lorazepam): prevention of acetaminophen toxicity by cimetidine.
Fourteen healthy volunteers received a single i.v. dose of antipyrine (1.2 g) on two occasions, once before and once during cimetidine treatment (300 mg every 6 hr). In a similar manner, 8 subjects received diazepam (10 mg), 11 subjects received acetaminophen (650 mg) and 8 subjects received lorazepam (2 mg), all by the i.v. route, once before and once during cimetidine coadministration. Pharmacokinetic analysis indicated increased antipyrine elimination T1/2 during cimetidine treatment (16.7 vs. 10.9 hr; P less than .001) on the basis of decreased total metabolic clearance (0.46 vs. 0.72 ml/min/kg; P less than .001). Likewise, diazepam T1/2 was increased (58 vs. 39 hr; P less than .01) during cimetidine treatment due to decreased total metabolic clearance (0.42 vs. 0.30 ml/min/kg; P less than .01). In contrast, cimetidine did not alter T1/2 or the clearance of lorazepam (T1/2, 16.8 vs. 15.3 hr; clearance, 1.03 vs 1.07 ml/min/kg) or acetaminophen (T1/2, 2.66 vs. 2.60 hr; clearance, 4.8 vs. 4.5 ml/min/kg), both drugs which undergo conjugative biotransformation. In an animal model used to assess the effect of cimetidine on acetaminophen toxicity, the LD50 of acetaminophen alone in Charles River CD-1 mice was 480 mg/kg (95% confidence interval: 436-528 mg/kg). With simultaneous 75 mg/kg of cimetidine treatment, the LD50 for acetaminophen was significantly increased (P less than .05) to 1020 mg/kg (95% confidence interval: 962-1081 mg/kg). Thus, cimetidine slows the metabolic clearance of antipyrine and diazepam, drugs biotransformed by hepatic oxidation, but does not alter the kinetics of acetaminophen or lorazepam, both metabolized by conjugation. Cimetidine may decrease the toxicity of high-dose acetaminophen by preventing formation of the hepatotoxic oxidative metabolites, although having no effect on conjugation of acetaminophen which yields nontoxic metabolites that are subsequently cleared from the body.
Acetaminophen↗
Obesity, sex, and acetaminophen disposition.
Twenty-one obese (14 women; 7 men) and 21 normal (11 women; 10 men) drug-free and age-matched subjects were given single 650-mg IV doses of acetaminophen. Mean total body weights (TBW) for the groups were as follows: obese men, 134.9 kg; control men 70.6 kg; obese women, 87.9 kg; and control women, 55.0 kg; ideal body weight (IBW) was similar for all of the groups. Acetaminophen elimination half-life (t1/2 beta) did not differ among groups. Absolute volume of distribution (Vd) was greater in obese than in control men (109 and 77 l, P less than 0.05) and greater in control men than in control women (77 and 52 l, P less than 0.05), but Vd corrected for TBW was smaller in obese than in control men (0.81 and 1.09 l/kg TBW, P less than 0.05) and smaller in obese than control women (0.71 and 0.95 l/kg TBW, P less than 0.05). Absolute metabolic clearance was greater in obese than in control men (484 and 323 ml/min, P less than 0.05), in obese than in control women (312 and 227 ml/min, P less than 0.05), and in control men than women (323 and 227 ml/min, P less than 0.05). After correction for TBW, however, clearance between control and obese subjects of the same sex did not differ. Acetaminophen Vd is increased in obesity and in men relative to women, but the drug's distribution into body weight exceeding IBW is less extensive than that into IBW. For men the distribution ratio is 0.44 and for women, 0.31. Acetaminophen clearance increases with body weight and therefore is much greater in obese patients and in men.
Acetaminophen↗
Acetaminophen kinetics in the elderly.
Thirty-two healthy men and women, 23 to 78 yr old, received single 650-mg intravenous doses of acetaminophen and the drug's kinetics were determined from multiple plasma samples drawn over the next 8 to 12 hr. Acetaminophen elimination half-life averaged 2.7 hr (range, 1.9 to 4.3 hr) and was not related to age or sex. Volume of distribution (corrected for weight) was larger in men than in women (0.99 and 0.86 l/kg) and declined with age in both sexes. This probably reflects increased fat per kilogram body weight in women and in the elderly, together with incomplete distribution of this nonlipophilic drug into body fat. Acetaminophen clearance tended to decline with age in both sexes, but differences were of borderline significance. On the basis of kinetics data alone, adjustment of acetaminophen dosage for the elderly is generally not necessary.
Acetaminophen↗