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1.
Clin Pharmacol Ther ; 93(3): 267-74, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23361101

ABSTRACT

Four popular ephedra-free dietary supplements were evaluated for their effects on heart rate (HR), blood pressure (BP), and electrocardiographic (ECG) parameters. Twelve healthy men participated in a study randomized for product sequence, with a 21-day washout period between supplement-administration phases. Throughout the study, Holter monitors were used to assess ECG and HR activity. BP was assessed automatically on multiple occasions. The supplements were ingested three times daily for 3 days. Caffeine content, microbial load, and serum caffeine concentrations were determined. Mean systolic (SBP) and diastolic BP (DBP) readings showed significant increases relative to baseline (10.8 ± 2.5 and 5.3 ± 3.1 mm Hg, respectively; P < 0.05). All supplements significantly increased HR and decreased bradycardia runs; abnormal atrial/ventricular events were frequently noted. Gastrointestinal and sympathomimetic symptoms were also common. Two supplements were heavily contaminated with Bacillus species. In light of these findings, the use of ephedra-free dietary supplements should be discouraged in individuals with hypertension, diabetes, or other cardiovascular diseases.


Subject(s)
Bacillus/isolation & purification , Blood Pressure/drug effects , Dietary Supplements , Drug Contamination , Electrocardiography/drug effects , Heart Rate/drug effects , Adult , Caffeine/blood , Cross-Over Studies , Dietary Supplements/microbiology , Humans , Male , Theophylline/blood
4.
Clin Pharmacol Ther ; 83(1): 61-9, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17495878

ABSTRACT

The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates.


Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Dietary Supplements , Enzyme Inhibitors/pharmacology , Herb-Drug Interactions , Hydrastis , Kava , Midazolam/pharmacokinetics , Plant Preparations/pharmacology , Adult , Clarithromycin/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Enzyme Induction/drug effects , Female , Humans , Male , Models, Biological , Phenotype , Rifampin/pharmacology , Risk Assessment , Substrate Specificity
5.
Pharmacology ; 67(4): 195-201, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12595750

ABSTRACT

A potential cytokine-drug interaction between interleukin 6 (IL-6) and itraconazole (ITZ) was studied using human hepatocytes in primary culture. Cultures from 5 adult males (mean age 42 +/- 15 years) who had not received any medicines known to interact with CYP3A4 were studied. Cultures were exposed to ITZ 500 ng/ml, and the effects of 120 microg/ml cimetidine, 50 ng/ml human IL-6, or IL-6 plus IL-6 receptor antagonist were analyzed for 2, 4, 8, and 12 h. Intracellular ITZ and hydroxyitraconazole concentrations were measured using HPLC and normalized to total cellular protein. Mean intracellular concentrations between groups were compared using one-way Anova (f test; p < 0.10) and corresponding Bonferroni versus control test for multiple comparisons (p < 0.02). Mean intracellular ITZ concentrations between the groups were similar at all time points. Human hepatocytes in primary culture can metabolize ITZ. However, IL-6 did not inhibit hydroxyitraconazole formation, but it may inhibit its subsequent metabolism.


Subject(s)
Hepatocytes/drug effects , Interleukin-6/pharmacology , Itraconazole/analogs & derivatives , Itraconazole/metabolism , Itraconazole/pharmacology , Liver/drug effects , Adult , Cells, Cultured , Cimetidine/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Enzyme Inhibitors/pharmacology , Hepatocytes/metabolism , Humans , Liver/cytology , Liver/metabolism , Male , Middle Aged , Receptors, Interleukin-6/antagonists & inhibitors
6.
J Clin Pharmacol ; 41(10): 1059-63, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11583473

ABSTRACT

The Seville orange extract Citrus aurantium contains m-synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to "knock out" intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high-performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 +/- 0.52 microg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. Individuals with severe hypertension, tachyarrhythmias, and narrow-angle glaucoma and monoamine oxidase inhibitor recipients should avoid SOJ consumption. Persons taking decongestant-containing cold preparations should also refrain from SOJ intake.


Subject(s)
Beverages/analysis , Cardiovascular System/drug effects , Citrus/chemistry , Synephrine/analysis , Synephrine/pharmacology , Vasoconstrictor Agents/analysis , Vasoconstrictor Agents/pharmacology , Adult , Analysis of Variance , Cross-Over Studies , Female , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Male , Plant Extracts/analysis , Plant Extracts/pharmacology , Synephrine/chemistry , Vasoconstrictor Agents/chemistry
7.
Transplantation ; 71(2): 239-41, 2001 Jan 27.
Article in English | MEDLINE | ID: mdl-11213066

ABSTRACT

BACKGROUND: Herbal dietary supplements represent a potential and possibly an overlooked cause for drug interactions in transplant recipients. METHODS: Two patients are reported which suggest that St. John's Wort (SJW) may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression. Both of these mechanisms are significantly involved in the metabolism and absorption of cyclosporine (CSA) and other immunosuppressants. RESULTS: After two renal transplant recipients started self-medicating with SJW, their CSA concentrations were consistently documented to be subtherapeutic. While on SJW, one patient developed acute graft rejection due to low CSA concentrations. In both patients, termination of SJW returned their CSA concentrations to therapeutic values. CONCLUSIONS: Patients taking SJW concomitantly with CSA or other medications whose absorption and metabolism are mediated by cytochrome P-450 and/or P-glycoprotein should require close monitoring. Potential herb-prescription drug interactions are not just limited to SJW. Inquiries regarding the usage of herbal supplements should be an integral component of a transplant recipient's medication history.


Subject(s)
Dietary Supplements , Phytotherapy , Adult , Drug Interactions , Drugs, Chinese Herbal/pharmacology , Female , Graft Rejection/drug therapy , Graft Rejection/prevention & control , Herb-Drug Interactions , Humans , Kidney Transplantation/immunology , Pancreas Transplantation/immunology
8.
J Clin Pharmacol ; 41(1): 113-5, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11144989

ABSTRACT

Acute intermittent porphyria results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis and is commonly exacerbated by a wide variety of medications. When referred a patient with acute intermittent porphyria for a renal transplant, only steroids and azathioprine were discovered as safe in patients with acute intermittent porphyria. The administration of many newer immunosuppressive medications, including calcineurin inhibitors, has not been documented in acute intermittent porphyria. Actually, cyclosporine is presently considered contraindicated in acute intermittent porphyria. To determine if calcineurin inhibitors would be tolerated in acute intermittent porphyria, cyclosporine and tacrolimus were administered pretransplant and were documented not to exacerbate acute intermittent porphyria. A successful renal transplant was then performed using tacrolimus. This is the first reported patient with documented acute intermittent porphyria to tolerate safely several of the newer immunosuppressive medications, including tacrolimus, mycophenolate, and rabbit antithymocytic globulin following renal transplantation. This patient's pretransplant evaluation also suggested that cyclosporine may be safe for some patients with acute intermittent porphyria.


Subject(s)
Cyclosporine/adverse effects , Immunosuppressive Agents/adverse effects , Porphyria, Acute Intermittent/physiopathology , Tacrolimus/adverse effects , Cyclosporine/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Kidney Transplantation , Male , Middle Aged , Porphyria, Acute Intermittent/complications , Tacrolimus/therapeutic use
9.
Prog Transplant ; 11(3): 214-6, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11949465

ABSTRACT

The pretransplant evaluation of a patient with a rare diagnosis requires knowledge of the pathophysiology and the transplant literature. A 55-year-old man presented with hypertensive kidney failure and the clinical diagnosis of acute intermittent porphyria. Complications of acute intermittent porphyria, which is a defect of heme production, are due to the accumulation of heme intermediates often precipitated by medications. Based on animal data, cyclosporine is considered unsafe in patients with acute intermittent porphyria. As part of the pretransplant evaluation, the patient received separate trials of tacrolimus and cyclosporine, which did not stimulate his acute intermittent porphyria. Four months after a kidney transplant, the patient still had no signs of rejection or symptoms of acute intermittent porphyria. This is the first documented patient with acute intermittent porphyria who successfully received a kidney transplant using tacrolimus. Because of individual variations, pretransplant testing of calcineurin inhibitors should be continued in patients with acute intermittent porphyria.


Subject(s)
Kidney Transplantation , Porphyria, Acute Intermittent/immunology , Tacrolimus/adverse effects , Aged , Cyclosporine/adverse effects , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Porphyria, Acute Intermittent/drug therapy , Preoperative Care , Tacrolimus/administration & dosage
10.
Prog Transplant ; 11(2): 116-20, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11871046

ABSTRACT

Herbal medications may cause prescription drug interactions in transplant recipients. After 2 of our kidney transplant recipients started self-medicating with St John's wort, their cyclosporine concentrations were consistently documented to be subtherapeutic. While on St John's wort, one patient developed acute rejection possibly due to low cyclosporine concentrations. Termination of St John's wort returned both patients' cyclosporine concentrations to therapeutic values. Based on the Naranjo Adverse Drug Reaction Probability Scale, our report would achieve a "probable" score, which supports the existence of a St John's wort-cyclosporine adverse drug interaction. St John's wort may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression, which are both involved in the metabolism and absorption of cyclosporine. Patients using St John's wort concomitantly with cyclosporine or other medications with similar absorption and/or metabolism to cyclosporine need close monitoring. Transplant coordinators are in a critical position to educate transplant recipients about the potential risks of herbal medication usage.


Subject(s)
Cyclosporine/pharmacokinetics , Graft Rejection/immunology , Hypericum/adverse effects , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Pancreas Transplantation , Plant Preparations/adverse effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Cytochrome P-450 Enzyme System/metabolism , Dietary Supplements , Drug Interactions , Female , Humans
11.
Ann Pharmacother ; 34(9): 1013-6, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10981246

ABSTRACT

OBJECTIVE: To report a probable drug interaction between the herbal dietary supplement St. John's wort and cyclosporine. CASE REPORT: A 29-year-old white woman who received a cadaveric kidney and pancreas transplant, with stable organ function and stable cyclosporine concentrations began self-medicating with St. John's wort. After taking St. John's wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. John's wort, her cyclosporine concentrations again became therapeutic. Subsequent to this rejection episode, she has developed chronic rejection and now has returned to dialysis. DISCUSSION: St. John's wort is suspected to be a significant inducer of CYP3A4 isoenzyme activity and of P-glycoprotein (P-gp) expression, both of which are important in the metabolism and absorption of cyclosporine. Cyclosporine exhibits a relatively small therapeutic window and is sensitive to medications that can modulate the CYP3A4 isoenzyme and P-gp in both the liver and small intestines. CONCLUSIONS: Patients taking St. John's wort concomitant with other prescription medications whose absorption and metabolism are mediated by the CYP3A4 isoenzyme and P-gp require close monitoring. Patient medication histories should include inquiries into the use of herbal dietary supplements.


Subject(s)
Cyclosporine/pharmacology , Hypericum/chemistry , Plants, Medicinal , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Cyclosporine/metabolism , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Female , Gene Expression/drug effects , Humans , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacology , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Organ Transplantation , Plant Extracts/pharmacology , Plants, Medicinal/chemistry
12.
Am J Health Syst Pharm ; 57(10): 963-9, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10832496

ABSTRACT

The content of ephedra alkaloids in herbal dietary supplements containing ephedra (ma huang) was studied. The ephedra alkaloid content of 20 ephedra-containing supplements was determined by high-performance liquid chromatography. Contents of (-)-ephedrine, (+)-pseudoephedrine, (-)-methylephedrine, (-)-norephedrine, and (+)-norpseudoephedrine were measured. Ephedra alkaloid content varied considerably among products. Total alkaloid content ranged from 0.0 to 18.5 mg per dosage unit. Ranges for (-)-ephedrine and (+)-pseudoephedrine were 1.1-15.3 mg and 0.2-9.5 mg, respectively. (+)-Norpseudoephedrine, a Schedule IV controlled substance, was often present. Significant lot-to-lot variations in alkaloid content were observed for four products. For one product, lot-to-lot variations in the content of (-)-ephedrine, (+)-pseudoephedrine, and (-)-methylephedrine exceeded 180%, 250%, and 1000%, respectively. Half of the products exhibited discrepancies between the label claim for ephedra alkaloid content and actual alkaloid content in excess of 20%. One product was devoid of ephedra alkaloids. Assay of 20 ephedra-containing dietary supplements showed that alkaloid content often differed markedly from label claims and was inconsistent between two lots of some products.


Subject(s)
Alkaloids/analysis , Dietary Supplements , Plants, Medicinal/chemistry , Drug Labeling , Drug and Narcotic Control , Ephedrine/analysis , Humans
13.
Ther Drug Monit ; 21(3): 304-9, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10365642

ABSTRACT

The systemic availability of itraconazole capsules may be reduced secondary to elevated gastric pH and possibly by presystemic intestinal metabolism via CYP3A4. Grapefruit juice is acidic and an inhibitor of intestinal CYP3A4. To determine the effect of grapefruit juice on the systemic availability of itraconazole capsules, serum itraconazole and hydroxy-itraconazole concentrations were determined in eleven healthy volunteers studied in a randomized, two-way crossover design. Concurrent grapefruit juice resulted in a 43% decrease in the mean itraconazole AUC0-48 (2507 ng x hr/mL versus 1434 ng x hr/mL, p = 0.046) and a 47% decrease in the mean hydroxy-itraconazole AUC0-72 (7264 ng x hr/mL versus 3880 ng x hr/mL, p = 0.025). Grapefruit juice also significantly increased the mean itraconazole Tmax (5.5 versus 4 hours). We conclude that concomitant grapefruit juice does not enhance the systemic availability of itraconazole capsules, but rather appears to impair itraconazole absorption. Therefore, concomitant grapefruit juice will not likely be useful in improving the oral availability of itraconazole capsules.


Subject(s)
Antifungal Agents/pharmacokinetics , Citrus , Itraconazole/pharmacokinetics , Adult , Biological Availability , Capsules , Cross-Over Studies , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Female , Humans , Hydrogen-Ion Concentration , Intestinal Absorption , Male , Mixed Function Oxygenases/metabolism , Reference Values
14.
Ther Drug Monit ; 20(4): 439-45, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9712471

ABSTRACT

Nutritional supplements containing Ephedra sinica (ma huang), a botanical source of ephedrine alkaloids, have been linked to several episodes of ephedrine toxicity and at least 17 deaths, yet these products remain unregulated. Ten subjects were enrolled in a randomized, crossover study aimed at characterizing the pharmacokinetics of ephedrine after the ingestion of three commercially available ma huang products compared with a 25-mg ephedrine capsule. Pharmacokinetic parameters for botanical ephedrine were similar to those for synthetic ephedrine hydrochloride. Gender-based comparisons of Vss/F and CL/F revealed higher values for women than for men (Vss/F, 3.49 +/- 1.04 vs 2.98 +/- 0.73 l/kg; CL/F, 0.48 +/- 0.11 vs 0.37 +/- 0.11 l/hour x kg). The current study suggests that the increased incidence of ma huang toxicity does not stem from differences in the absorption of botanical ephedrine compared with synthetic ephedrine; rather, it results from accidental overdose often prompted by exaggerated off-label claims and a belief that "natural" medicinal agents are inherently safe.


Subject(s)
Alkaloids/pharmacokinetics , Ephedrine/pharmacokinetics , Sympathomimetics/pharmacokinetics , Adult , Alkaloids/administration & dosage , Alkaloids/blood , Cross-Over Studies , Dietary Supplements , Ephedrine/administration & dosage , Ephedrine/blood , Female , Humans , Male , Plants, Medicinal , Sex Factors , Sympathomimetics/administration & dosage , Sympathomimetics/blood
16.
J Pharm Biomed Anal ; 16(6): 1005-12, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9547703

ABSTRACT

Published high performance liquid chromatographic (HPLC) methods for the determination of itraconazole (ITZ) in biological matrices are labor intensive, extraction-based procedures which operate at a pH approaching the limit of column tolerance, and unless modified, cannot measure its hydroxy-metabolite (OH-ITZ). A protein precipitation-based method requiring no solvent extraction and utilizing a base-deactivated C18 analytical column to minimize peak tailing is described herein. Calibration curves for OH-ITZ and ITZ were linear from 25-1500 ng ml-1 (r2 > or = 0.999). Intra-assay relative standard deviations (R.S.D.) were below 12%. Inter-assay R.S.D. were below 14%. This method provides a rapid means for the accurate and precise determination of both OH-ITZ and ITZ concentrations in human serum.


Subject(s)
Antifungal Agents/blood , Itraconazole/analogs & derivatives , Calibration , Chromatography, High Pressure Liquid , Humans , Hydroxylation , Indicators and Reagents , Itraconazole/blood , Quality Control , Reference Standards , Reproducibility of Results
17.
Am J Health Syst Pharm ; 55(3): 261-5, 1998 Feb 01.
Article in English | MEDLINE | ID: mdl-9492256

ABSTRACT

The bioavailability of itraconazole from an extemporaneously prepared suspension was compared with its bioavailability from the commercially available capsules. Ten healthy volunteers were fed breakfast and were then randomly assigned to receive either 400 mg of itraconazole 40-mg/mL oral suspension or four 100-mg itraconazole capsules with 240 mL of water. They were not allowed to rest in a supine position for six hours, eat for four hours, or take any beverages for two hours post-dose. Blood samples were taken immediately after the subjects had eaten and at intervals up to 72 hours post-dose. Serum was separated and stored at -70 degrees C. Serum itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography. After 14 days, each subject was given the dosage form that he or she did not previously receive, and testing was repeated. Maximum concentration (Cmax) and time to reach maximum concentration (tmax) were determined, and the area under the serum concentration-versus-time curve from 0 to 72 hours (AUC0-72) was estimated. The suspension:capsule ratios of least-squares means for Cmax, tmax, and AUC0-72 for itraconazole were 0.15 (90% confidence interval [CI], 0.11-0.21), 0.95 (90% CI, 0.75-1.20), and 0.12 (9% CI, 0.06-0.23), respectively. The results for hydroxyitraconazole were similar: 0.19 (0.13-0.28), 0.95 (0.81-1.12), and 0.13 (0.07-0.23), respectively. The bioavailability of itraconazole from the extemporaneously prepared suspension is much lower than that from capsules.


Subject(s)
Antifungal Agents/pharmacokinetics , Itraconazole/pharmacokinetics , Adult , Area Under Curve , Capsules , Drug Compounding , Female , Humans , Male , Metabolic Clearance Rate , Middle Aged , Suspensions , Therapeutic Equivalency
18.
J Pharm Sci ; 87(12): 1547-53, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10189265

ABSTRACT

Nutritional supplements containing Ephedra sinica (ma-huang), a botanical source of ephedrine-type alkaloids, have been linked to numerous episodes of ephedrine (EPH) toxicity. With passage of the 1994 Dietary Supplement Health and Education Act, nutritional supplements are no longer subject to the same FDA preapproval requirements as food additives, prescription, or nonprescription medications. As a consequence, EPH content is not a label requirement for Ephedra-containing supplements. Less stringent labeling requirements, therefore, may contribute to toxicity associated with these products. A validated HPLC method for the determination of ephedrine-type alkaloids, commonly found in Ephedra supplements, is presented. Nine commercially available supplements exhibited considerable variability in alkaloid content (EPH range: 1.08-13.54 mg). Only three products listed EPH content on the label while one exhibited lot to lot variations in EPH of 137%.


Subject(s)
Alkaloids/analysis , Chromatography, High Pressure Liquid , Dietary Supplements/standards , Ephedra sinica , Ephedrine/analogs & derivatives , Ephedrine/chemistry , Evaluation Studies as Topic , Plant Extracts/chemistry , Plant Preparations , Reproducibility of Results
19.
J Clin Pharmacol ; 37(2): 116-22, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9055137

ABSTRACT

The purpose of this study was to evaluate heart rate and blood pressure responses to a commercially available source of ma-haung, a natural source of the sympathomimetic substance, ephedrine, and to evaluate the pharmacokinetic properties of the product in normotensive, healthy adults. On day 1, twelve study participants were monitored with an ambulatory blood pressure device between hours 7 and 20. On day 2, they ingested four capsules of powdered ma-huang at hours 8 and 17 while again wearing the monitor between hours 7 and 20. Serial plasma samples were obtained and concentrations of ephedrine were analyzed by high-performance liquid chromatography. Pharmacokinetic parameters of ephedrine were determined from plasma concentration-time profiles. The ephedrine alkaloid content of each capsule was also determined by high-performance liquid chromatography. Six participants experienced a statistically significant increase in heart rate, but the effects on blood pressure were variable. The half-life, volume of distribution, clearance, and maximum concentration in plasma of ephedrine in the ma-huang product were similar to values previously reported for a 20 mg, immediate-release ephedrine tablet. Values for the absorption rate were considerably lower and time to reach maximum concentration was longer for the capsules, compared with the standard tablet. Variability in alkaloid content of ephedrine was low and yielded a mean dose of ephedrine at 19.4 mg; pseudoephedrine at 4.9 mg; and methylephedrine at 1.2 mg for a four-capsule dose. In summary, ma-haung had variable effects on blood pressure and increased heart rate in healthy, normotensive adults. Pharmacokinetic parameters for ephedrine were in agreement with those previously reported; however, the absorption rate was much slower after ingestion of ma-huang.


Subject(s)
Blood Pressure/drug effects , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacokinetics , Ephedra sinica , Ephedrine/administration & dosage , Ephedrine/pharmacokinetics , Heart Rate/drug effects , Adult , Area Under Curve , Blood Pressure Monitoring, Ambulatory , Capsules/analysis , Capsules/standards , Drugs, Chinese Herbal/analysis , Ephedrine/analysis , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Plant Preparations , Sympathomimetics/analysis
20.
Pharm Res ; 14(1): 67-72, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9034223

ABSTRACT

PURPOSE: All transplanted solid organs experience some degree of ischemia-reperfusion (I-R) injury. This I-R injury can contribute to graft dysfunction which stems in part from the acute phase response and a resultant host of cytokines. Recent evidence suggests that organs remote to the site of I-R injury can be affected by circulating cytokines originating from these I-R injuries. Since many of these acute phase cytokines inhibit hepatic cytochrome P-450 (CYP) enzymes, we chose to investigate whether extrahepatic I-R injuries could influence hepatic oxidative drug metabolism. METHODS: Fifteen dogs were divided into three surgical groups: (I) sham I-R; (II) bilateral normothermic renal I-R; and (III) normothermic intestinal I-R. Antipyrine (AP) was selected as a model substrate and administered intravenously at a dose of 10 mg/kg. AP serum concentrations were determined by HPLC and cytokine activity (IL-1, IL-6, and TNFalpha) was measured via bioassay. Serial AP clearance and serum cytokine concentrations were determined 3 days prior to and at 4 hr, 24 hr, 3 days and 7 days after surgery. Hematology and blood chemistries were monitored throughout the study period. RESULTS: AP clearance was significantly reduced in groups II and III at 4 and 24 hrs post-l-R injury, while AP binding and apparent volume of distribution were unaffected. Peak levels of TNF and IL-6 activity occurred at 1 and 4 hours, respectively. IL-I activity was not detected in any group. AP clearance correlated strongly to circulating levels of IL-6 (r = -0.789, p = 0.0002). CONCLUSIONS: Our findings indicate that extrahepatic I-R injury can affect hepatic oxidative drug metabolism and this effect is mediated in part by circulating cytokines.


Subject(s)
Antipyrine/pharmacokinetics , Liver/metabolism , Reperfusion Injury/metabolism , Animals , Antipyrine/blood , Dogs , Interleukin-1/blood , Interleukin-6/blood , Intestines/blood supply , Kidney/blood supply , Liver/blood supply , Male , Oxidation-Reduction , Tumor Necrosis Factor-alpha/analysis
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