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British Journal of Clinical Pharmacology Sep 2015It is common to advise that analgesics, and especially non-steroidal anti-inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse... (Review)
Review
AIMS
It is common to advise that analgesics, and especially non-steroidal anti-inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states.
METHODS
A systematic review of comparisons of oral analgesics in fed and fasting states published to October 2014 reporting kinetic parameters of bioavailability, time to maximum plasma concentration (tmax ), and its extent (Cmax ) was conducted. Delayed-release formulations were not included.
RESULTS
Bioavailability was not different between fasted and fed states. Food typically delayed absorption for all drugs where the fasting tmax was less than 4 h. For the common analgesics (aspirin, diclofenac, ibuprofen, paracetamol) fed tmax was 1.30 to 2.80 times longer than fasted tmax . Cmax was typically reduced, with greater reduction seen with more rapid absorption (fed Cmax only 44-85% of the fasted Cmax for aspirin, diclofenac, ibuprofen and paracetamol).
CONCLUSION
There is evidence that high, early plasma concentrations produces better early pain relief, better overall pain relief, longer lasting pain relief and lower rates of remedication. Taking analgesics with food may make them less effective, resulting in greater population exposure. It may be time to rethink research priorities and advice to professionals, patients and the public.
Topics: Acetaminophen; Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biological Availability; Dipyrone; Drug Liberation; Food-Drug Interactions; Humans
PubMed: 25784216
DOI: 10.1111/bcp.12628 -
Allergy, Asthma, and Clinical... Mar 2021For a century, epinephrine has been the drug of choice for acute treatment of systemic allergic reactions/anaphylaxis. For 40 years, autoinjectors have been used for... (Review)
Review
BACKGROUND
For a century, epinephrine has been the drug of choice for acute treatment of systemic allergic reactions/anaphylaxis. For 40 years, autoinjectors have been used for the treatment of anaphylaxis. Over the last 20 years, intramuscular epinephrine injected into the thigh has been recommended for optimal effect.
OBJECTIVE
To review the literature on pharmacokinetics of epinephrine autoinjectors.
RESULTS
Six studies assessing epinephrine autoinjector pharmacokinetics were identified. The studies, all on healthy volunteers, were completed by Simons, Edwards, Duvauchelle, Worm and Turner over the span of 2 decades. Simons et al. published two small studies that suggested that intramuscular injection was superior to subcutaneous injection. These findings were partially supported by Duvauchelle. Duvauchelle showed a proportional increase in C and AUC when increasing the dose from 0.3 to 0.5 mg epinephrine intramuscularly. Turner confirmed these findings. Simons, Edwards and Duvauchelle documented the impact of epinephrine on heart rate and blood pressure. Turner confirmed a dose-dependent increase in heart rate, cardiac output and stroke volume. Based on limited data, confirmed intramuscular injections appeared to lead to faster C. Two discernable C were identified in most of the studies. We identified similarities and discrepancies in a number of variables in the aforementioned studies.
CONCLUSIONS
Intramuscular injection with higher doses of epinephrine appears to lead to a higher C. There is a dose dependent increase in plasma concentration and AUC. Most investigators found two C with T 5-10 min and 30-50 min, respectively. There is a need for conclusive trials to evaluate the differences between intramuscular and subcutaneous injections with the epinephrine delivery site confirmed with ultrasound.
PubMed: 33685510
DOI: 10.1186/s13223-021-00511-y -
Integrative Medicine (Encinitas, Calif.) Nov 2022The science of the metabolism of CoQ10 before and after its absorption into the blood is well known. Almost nothing is known about the absorption of CoQ10 into the lymph. (Review)
Review
CONTEXT
The science of the metabolism of CoQ10 before and after its absorption into the blood is well known. Almost nothing is known about the absorption of CoQ10 into the lymph.
OBJECTIVE
The study intended to measure and compare the single-dose absorption of three CoQ10 product formulations-crystal-free ubiquinone, crystalline ubiquinol, and a dry-powder ubiquinone-into the abdominal lymph duct as compared to their absorption into the blood circulation.
DESIGN
The researcher designed an animal study.
ANIMALS
The animals were six large dogs (>50 Kg).
INTERVENTION
By gastric gavage, the dogs were given a 100-mg dose of either crystal-free ubiquinone (Q-Best), crystalline ubiquinol (Qunol), or dry-powder ubiquinone, and lymph and venous samples (5 ml) were collected.
OUTCOME MEASURES
The primary end-point measurements for three CoQ10 product types were the concentration (Cmax), time of Cmax (Tmax), and total CoQ10 absorbed into the lymph and that transported to the blood.
RESULTS
Coenzyme Q10 (CoQ10) crystals were found in the dry powder and crystalline ubiquinol formulations. No crystals were found in the crystal-free formulation. Crystals from both the crystalline and dry-powder formulations were found in the small intestine's chyme. After ingestion of a 100-mg dose of CoQ10 formulation, the group mean absorption into the lymph peaked in 2 hours for all three formulations, and the peak appearance (Cmax) in the blood occurred at 6 hours. The absorption was significantly ( ≤ .001) greater for the crystal-free formulation compared to that of the crystalline and dry-powder formulations measured in the lymph and plasma.
CONCLUSIONS
These data show that the crystal-free formulation's absorption is superior to that found for the other two formulations. These results show that CoQ10 crystals are the causative factor for the poor absorption of CoQ10. The delayed appearance in the blood is due to the slow lymph flow delivering CoQ10 to the blood. The absorption of CoQ10 may not be as poor as described in the literature.
PubMed: 36643212
DOI: No ID Found -
Drug Metabolism and Drug Interactions 2014To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone. (Review)
Review
BACKGROUND
To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone.
METHODS
Seven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (Cmax) and area under the concentration-time curve (AUC) were calculated.
RESULTS
Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone Cmax and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1- and 2.2-fold increases, respectively. Rifampin decreased lurasidone Cmax and AUC (one-seventh and one-fifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased Cmax and AUC0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate).
CONCLUSIONS
Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment for lurasidone is needed when administered with lithium or valproate. Dose adjustment is not required for lithium, valproate, digoxin (a P-glycoprotein substrate), or midazolam or oral contraceptives (CYP3A4 substrates) when coadministered with lurasidone.
Topics: Antipsychotic Agents; Area Under Curve; Clinical Trials, Phase I as Topic; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Diltiazem; Drug Interactions; Drug Therapy, Combination; Humans; Isoindoles; Ketoconazole; Lithium Compounds; Lurasidone Hydrochloride; Rifampin; Thiazoles
PubMed: 24825095
DOI: 10.1515/dmdi-2014-0005 -
AIDS Research and Human Retroviruses Jan 2020We investigated the use of a system with an ingestible sensor (Proteus Digital Health Feedback system) coencapsulated with antiretrovirals (ARVs) to measure real-time...
We investigated the use of a system with an ingestible sensor (Proteus Digital Health Feedback system) coencapsulated with antiretrovirals (ARVs) to measure real-time adherence. To assess the safety and impact, if any, coencapsulation might have on ARV concentrations, we evaluated the pharmacokinetics of ARVs coencapsulated with an ingestible sensor for eight commonly used fixed-dose combination ARVs: emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF); FTC/tenofovir alafenamide (TAF); efavirenz (EFV)/FTC/TDF; abacavir (ABC)/lamivudine (3TC); dolutegravir (DTG)/ABC/3TC; rilpivirine (RPV)/TAF/FTC; elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF; and bictegravir (BIC)/FTC/TAF. The steady-state apparent peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were determined from plasma concentrations measured at predose, 1, 2, 4, and 6 h postdose, and compared with literature values. A total of 49 unique patients on stable regimens for at least 12 weeks with undetectable viral loads were recruited. Cmax and AUC values were not statistically significantly different from literature values for all of the formulations except the Cmax of FTC/TDF, Cmax of BIC, and the Cmax of RPV. In a subsequent evaluation of FTC/TDF and BIC/FTC/TAF using a crossover design, the geometric mean ratio (GMR) between the coencapsulated and the unencapsulated formulations for FTC/TDF were the following: FTC, 84.6% (90% confidence interval [CI] 66.6-107.4) for AUC and 77.5% (60.1-99.9) for Cmax. For tenofovir (TFV), the GMR was 96.2% (90% CI 89.2-103.8) for AUC and 87.3% (64.2-118.7) for Cmax. The GMR for BIC (from the BIC/FTC/TAF formulation) was 98.0% (90% CI 84.5-113.5) for AUC and 89.9% (84.5-95.7) for Cmax. The observed deviation in FTC/TDF (Truvada) may be due to participant characteristics, fasted/fed conditions, and/or random variation and may warrant further investigations with a larger sample size. These findings provide assurance for use of coencapsulated ARVs for future HIV treatment-adherence research.
Topics: Adult; Anti-HIV Agents; Biosensing Techniques; Cross-Over Studies; Drug Carriers; Drug Compounding; Drug Monitoring; Eating; Female; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; Monitoring, Ambulatory; Viral Load
PubMed: 31516025
DOI: 10.1089/AID.2019.0202 -
MedRxiv : the Preprint Server For... Feb 2023In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of cannabidiol (CBD) and explore the impact of different factors on...
BACKGROUND
In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of cannabidiol (CBD) and explore the impact of different factors on PK outcomes.
MATERIALS AND METHODS
This systematic review and meta-regression analysis was pre-registered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsychInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including Tmax, Cmax, AUC0-t, AUC0-inf, and T , in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The was used. Random-effects multivariable meta-regression analysis was conducted.
RESULTS
A total of 112 trial arms from 39 studies were included; 26 trial arms had a "Good" quality, 70 "Fair," and 16 "Poor." Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech (n=14), oil-based (n=21), alcohol-based (n=10), water-based (n=12), Sativex (n=17), and Epidiolex (n=22). For single-dose studies, CBD doses ranged between 2-100mg in inhalation, 5-50mg in oromucosal, and 0.42-6000mg in oral administration. Sixty-six trial arms had only male participants or a higher number of males than females. The duration of the PK session was between 4h-164h. A higher CBD dose was associated with higher Cmax, AUC0-t, and AUC0-inf. Compared to oral administration, oromucosal administration was associated with lower Cmax, AUC0-t, and AUC0-inf. Fed status was associated with higher Cmax and AUC0-t when compared to the fasting status. A higher ratio of female participants was associated with lower Tmax in oral administration and higher Cmax.
CONCLUSION
As expected, CBD dose, route of administration, and diet were major determinants of CBD pharmacokinetics with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Though CBD appeared to have a faster onset and longer duration in females, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.
PubMed: 36778355
DOI: 10.1101/2023.02.01.23285341 -
ALTEX 2023Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak...
Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak plasma concentration (Cmax) values for xenobiotics and comparing these values with in vitro-based toxicity endpoints. Herein, the authors predicted the Cmax values of food-related compounds in humans based on existing and novel in vitro techniques. In this study, 20 food-related compounds, which have been previously reported in human pharmacokinetic or toxicokinetic studies, were evaluated. Human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIEC) and Caco-2 cells, HepaRG cells, equilibrium dialysis of human plasma, and LLC-PK1 cell monolayer were used to assess intestinal absorption and availability, hepatic metabolism, unbound plasma fraction, and secretion and reabsorption in renal tubular cells, respectively. After conversion of these parameters into human kinetic parameters, the plasma concentration profiles of these compounds were predicted using in silico methods, and the obtained Cmax values were found to be between 0.017 and 183 times the reported Cmax values. When the in silico-predicted parameters were modified with in vitro data, the predicted Cmax values came within 0.1-10 times the reported values because the metabolic activities of hiPSC-SIECs, such as uridine 5’-diphospho-glucuronosyl transferase, are more similar to those of human primary enterocytes. Thus, combining in vitro test results with the plasma concentration simulations resulted in more accurate and transparent predictions of Cmax values of food-related compounds than those obtained using in silico-derived predictions alone. This method facilitates accurate safety evaluation without the need for animal experiments.
Topics: Animals; Humans; Computer Simulation; Caco-2 Cells; Induced Pluripotent Stem Cells; Administration, Oral; Food; Models, Biological
PubMed: 37216287
DOI: 10.14573/altex.2302131 -
Journal of Analytical Toxicology Oct 2020Total urinary 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) concentrations are generally reported following cannabis administration. Few data are available for...
Total urinary 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) concentrations are generally reported following cannabis administration. Few data are available for glucuronide and minor cannabinoid metabolite concentrations. All urine specimens from 11 frequent and 9 occasional cannabis users were analyzed for 11 cannabinoids for ~85 h by liquid chromatography with tandem mass spectrometry following controlled smoked, vaporized or oral 50.6 mg Δ9-tetrahydrocannabinol (THC) in a randomized, placebo-controlled, within-subject dosing design. No cannabidiol, cannabinol, cannabigerol, tetrahydrocannabivarin (THCV), THC, 11-OH-THC and Δ9-tetrahydrocannabinolic acid were detected in urine. Median THCCOOH-glucuronide maximum concentrations (Cmax) following smoked, vaporized and oral routes were 68.0, 26.7 and 360 μg/L for occasional and 378, 248 and 485 μg/L for frequent users, respectively. Median time to specific gravity-normalized Cmax (Tmax) was 5.1-7.9 h for all routes and all users. Median Cmax for THCCOOH, THC-glucuronide and 11-nor-9-carboxy-Δ9-THCV (THCVCOOH) were <7.5% of THCCOOH-glucuronide Cmax concentrations. Only THC-glucuronide mean Tmax differed between routes and groups, and was often present only in occasional users' first urine void. Multiple THCCOOH-glucuronide and THCCOOH peaks were observed. We also evaluated these urinary data with published models for determining recency of cannabis use. These urinary cannabinoid marker concentrations from occasional and frequent cannabis users following three routes of administration provide a scientific database to assess single urine concentrations in cannabis monitoring programs. New target analytes (CBD, CBN, CBG, THCV and phase II metabolites) were not found in urine. The results are important to officials in drug treatment, workplace and criminal justice drug monitoring programs, as well as policy makers with responsibility for cannabis regulations.
Topics: Administration, Oral; Adult; Cannabidiol; Cannabinoids; Cannabinol; Cannabis; Glucuronides; Humans; Marijuana Smoking; Smoke; Substance Abuse Detection
PubMed: 32369162
DOI: 10.1093/jat/bkaa046 -
Medicine Jul 2021Curcuminoids have been widely studied for human health and disease applications, yet bioavailability remains a hurdle to actualizing all the benefits ascribed to them....
BACKGROUND
Curcuminoids have been widely studied for human health and disease applications, yet bioavailability remains a hurdle to actualizing all the benefits ascribed to them. The lack of standardization in analysis method, confusion about what constitutes an ideal analyte, and conflicting thoughts around dosing strategies have made it difficult to draw parity between bioavailability and bioactivity and establish a baseline for formulation comparisons.
METHODS
This randomized double-blinded, 2-way cross over, single oral dose, comparative bioavailability study differentially evaluates curcumin at the time of its absorption and along various biotransformation pathways, to include free curcumin, the readily usable form of curcumin; individual and composite totals of curcumin and its analogues as exogenously cleaved conjugates, for example, total curcumin, total demethoxycurcumin (DMC), total bisdemethoxycurcumin (BDMC), and total curcuminoids respectively; and the bioactive metabolite of curcumin, total tetrahydrocurcumin (THC). As a primary study objective, the relative bioavailability of CURCUGEN, a novel dispersible, 50% curcuminoids-concentrated turmeric extract was compared to the standard curcumin reference product, curcuminoids 95% standardized extract (C-95), using the maximum concentration (Cmax), and area under the curve (AUC0-t) of free curcumin, total curcumin, total DMC, total BDMC and the curcumin active metabolite, as total THC.
RESULTS
The evaluation of free curcumin demonstrated that the Cmax and AUC0-t of the CURCUGEN was 16.1 times and 39 times higher than the Cmax and AUC0-t of C-95. Furthermore, total curcumin, total DMC, total BDMC, and total curcuminoids resulted in AUC0-t of the CURCUGEN at 49.5-, 43.5-, 46.8-, and 52.5-fold higher than C-95, respectively. The relative bioavailability of CURCUGEN for total THC was found to be 31 times higher when compared to C-95.
CONCLUSION
As the first human pharmacokinetics study to apply best-practice recommendations and pharmaceutically-aligned guidance in the comprehensive evaluation of a novel curcuminoids formulation, we have established the novelty of said formulation while better standardizing for the common variances and discrepancies between curcuminoids and their derivatives in the literature and commercial marketing, alike.
Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Cross-Over Studies; Curcumin; Double-Blind Method; Humans; Male; Middle Aged; Plant Extracts; Young Adult
PubMed: 34232211
DOI: 10.1097/MD.0000000000026601 -
Infectious Diseases and Therapy Aug 2022The correlation between total and free polymyxin B (PMB including PMB1 and PMB2) exposure in vivo and acute kidney injury (AKI) remains obscure. This study explores the...
INTRODUCTION
The correlation between total and free polymyxin B (PMB including PMB1 and PMB2) exposure in vivo and acute kidney injury (AKI) remains obscure. This study explores the relationships between plasma exposure of PMB1 and PMB2 and nephrotoxicity, and investigates the risk factors for PMB-induced acute kidney injury (AKI) in critically ill patients.
METHODS
Critically ill patients who used PMB and met the criteria were enrolled. The total plasma concentration and plasma binding of PMB1 and PMB2 were analysed by liquid chromatography-tandem mass spectrometry and equilibrium dialysis.
RESULTS
A total of 89 patients were finally included, and AKI developed in 28.1% of them. The peak concentration of PMB1 (C (B1)) (adjusted odds ratio (AOR) = 1.68, 95% CI 1.08-2.62, p = 0.023), baseline BUN level (AOR = 1.08, 95% CI 1.01-1.16, p = 0.039) and hypertension (AOR = 3.73, 95% CI 1.21-11.54, p = 0.022) were independent risk factors for PMB-induced AKI. The area under the ROC curve of the model was 0.799. When C (B1) was 5.23 μg/ml or more, the probability of AKI was higher than 50%. The ratio of PMB1/PMB2 decreased after PMB preparation entered into the body. The protein binding rate in critically ill patients indicated significant individual differences. Free C (B) and free C (B1) levels in the AKI group were significantly (p < 0.05) higher than those in the non-AKI group. Total and free concentrations of PMB in patients showed a positive correlation.
CONCLUSIONS
Both the ROC curve and logistic regression model showed that C (B1) was a good predictor for the probability of PMB-induced AKI. Early therapeutic drug monitoring (TDM) of PMB should be considered in critically ill patients. Compared with C (B), C (B) and C (B1) may be helpful for the early prediction of PMB-induced AKI in critically ill patients.
PubMed: 35689791
DOI: 10.1007/s40121-022-00655-3