Pharmacokinetic Investigation of Commercially Available Edible Marijuana Products in Humans: Potential Influence of Body Composition and Influence on Glucose Control

The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana on glucose tolerance. Seven regular users of marijuana self-administered five edible products in a randomized crossover design; each product contained 10 mg of delta-9-tetrahydrocannabinol (THC). Thirty minutes following marijuana ingestion, participants imbibed a 75 g glucose beverage. Time-to-peak plasma THC concentration ranged between 35 and 90 min; maximal plasma THC concentration (Cmax) ranged between 3.2 and 5.5 ng/mL. Differences between products in plasma THC concentration during the first 20–30 min were detected (p = 0.019). Relations were identified between body composition and pharmacokinetic parameters for some products; however, none of these body composition characteristics were consistently related to pharmacokinetics across all five of the products. Edible marijuana had no effect on oral glucose tolerance compared with a marijuana-free control (Matsuda Index; p > 0.395). Commercially available edible marijuana products evoke different plasma THC concentrations shortly after ingestion, but do not appear to influence acute glucose regulation. These data may allow recreational marijuana users to make informed decisions pertaining to rates of edible marijuana ingestion and avoid overdose.

Pharmacokinetic Investigation of Commercially Available Edible Marijuana Products in Humans: Potential Influence of Body Composition and Influence on Glucose Control

The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana on glucose tolerance. Seven regular users of marijuana self-administered five edible products in a randomized crossover design; each product contained 10mg of delta-9-tetrahydrocannabinol (THC). 30-minutes following marijuana ingestion, participants imbibed a 75g glucose beverage. Time-to-peak plasma THC concentration ranged between 35 and 90 minutes; maximal plasma THC concentration (Cmax) ranged between 3.2 and 5.5 ng/mL. Differences between products in plasma THC concentration during the first 20-to-30 minutes were detected (P=0.019). Relations were identified between body composition and pharmacokinetic parameters for some products; however, none of these body composition characteristics were consistently related to pharmacokinetics across all five of the products. Edible marijuana had no effect on oral glucose tolerance compared with a marijuana-free control (Matsuda Index; P>0.395). Commercially available edible marijuana products evoke different plasma THC concentrations shortly after ingestion, but do not appear to influence acute glucose regulation. These data may allow marijuana users to make informed decisions pertaining to rates of edible marijuana ingestion and avoid overdose.

Assessment of Chronic Supraphysiological Glucocorticoid Dosing Needs of Patients With Adrenal Insufficiency

Background: Patients who require higher than replacement glucocorticoid doses to avoid symptoms of adrenal insufficiency (AI) may have inadequate adherence or abnormal drug absorption or metabolism. The goal of this study was to identify why excessive glucocorticoid doses were needed in patients with ongoing AI symptoms. Methods: We performed pharmacokinetic (PK) analysis of glucocorticoid plasma concentrations (prednisone, prednisolone and dexamethasone measured by tandem mass spectrometry, Mayo Laboratories, and cortisol by immunoassay, Clinical Center) in 8 AI patients after weight-based oral hydrocortisone (HC) dose (1), IV HC 20 mg and /or prednisone 5 mg PO. The time (Tmax) to maximal plasma concentrations (Cmax), time to a 50% decrease in concentration (T1/2), elimination rate (ER) and area under the concentration curve (AUC) were determined using MATLAB and SimBiology, and compared to literature reference ranges (RR) (1,2). Results: Patients included one man; six had secondary AI due to previous supraphysiologic hydrocortisone or prednisone treatment and two had primary autoimmune AI. One of the latter was appropriately replaced with thyroid hormone. No patient was taking any medication known to be a strong inhibitor or inducer of CYP3A4 and none were taking oral estrogens. To study the potential contribution of intestinal absorption to abnormal pharmacokinetics, serum cortisol values were compared to expected values at 3.5 or 4 hours after a weight-based oral dose of HC in eight patients (1); 7 patients had values at the 50 - 80th centile of expected values. The eighth patient’s cortisol level at 4 hours after 5 mg HC was 30.3 nmol/L, below the 10th centile. She then underwent the same sampling with a 15 mg dose, with values also at the 10th centile. To uncover any discrepancy between PK oral and IV HC administration, four patients, including the patient with a low 4 hour value (LowHC4h) underwent sampling after 20 mg hydrocortisone, IV (2). Tmax and Cmax were within the RR in all four patients, while one patient had a faster T1/2 but an AUC similar to others. The LowHC4h patient had a dexamethasone level 8 hours after a 1 mg dose that was also within the RR and was maintained on dexamethasone. All others were eventually able to be weaned to a conventional glucocorticoid replacement dose. Conclusions: Evaluation of oral and IV HC PK may be useful in patients suspected of having abnormal absorption of oral glucocorticoids. Ref: 1. Mah PM et al. Clin Endo 61:367,20042. Thomson AH et al. Clin Endo 66:789,2007

Bioavailability of Orally Administered Active Lipid Compounds from four Different Greenshell™ Mussel Formats

Greenshell™ mussel (GSM, Perna canaliculus) is New Zealand’s most important aquaculture species. They are a good source of long chain-polyunsaturated fatty acids (n-3 LC PUFA). Beyond a traditional food product, GSMs are also sold as mussel powders and oil extract formats in the nutraceutical markets. In this study, a four-sequence, single dose, randomized crossover human trial with eight evaluable healthy male participants was undertaken to determine the bioavailability of the n-3 LC PUFA in four different GSM formats (oil, powder, food ingredient and half-shell unprocessed whole mussel) by measuring area under the curve (AUC) and maximal concentration (CMax). Blood samples were collected at baseline and up to 48 h after initiation of product consumption in each administration period. There were minor differences between the bioavailability of FA (fatty acid) between the different GSM formats. Eicosapentaenoic acid (EPA) peak concentrations and plasma exposures were significantly lower with GSM oil compared to GSM half-shell and GSM powder formats, which resulted in AUC0–48 for the intake of GSM half-shell mussel and GSM powder being significantly higher than that for GSM oil (p = 0.013, f= 4.84). This equated to a 20.6% and 24.3% increase in the amount of EPA present in the plasma after consumption of half-shell mussels and mussel powder respectively compared to GSM oil. GSM oil produced the shortest median time to maximal plasma n-3 LC PUFA concentration of all evaluated products demonstrated by a shorter maximum measured plasma concentration (TMax = 5 h). Docosahexaenoic acid (DHA) and n-3 LC PUFA plasma exposure parameters were statistically comparable across the four GSM products evaluated.

Pharmacokinetics and pharmacodynamics of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD), and there are no reliable preventive treatments. We uncovered a STAT3/CCAAT-enhancer-binding protein-δ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small-molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment for CKD-induced cachexia, we measured TTI-101 pharmacokinetics and pharmacodynamics in control and CKD rats that were orally administered TTI-101or its diluent. The following two groups of gavage-fed rats were studied: sham-operated control rats and CKD rats. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8, and 24 h) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS, and pharmacokinetic results were analyzed with the PKSolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations and time to maximal plasma levels (~1 h) were similar in sham-operated control rats and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham control rats and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg·kg−1·day−1 for 7 days. These results with TTI-101 in rats warrant its development as a treatment for cachexia in humans.

Pharmacokinetics of low-dose and high-dose buprenorphine in cats after rectal administration of different formulations

Objectives A prospective experimental study was performed in nine young healthy cats to investigate a pharmacokinetic profile and the clinical relevance of rectally administered buprenorphine. Rectal pH value was measured in all nine cats. Methods Blood was collected 15, 30, 60, 90, 120, 240 and 480 mins and 24 h after the rectal administration of a suppository and a gel at doses between 0.02 mg/kg and 0.1 mg/kg buprenorphine to determine the plasma concentration of buprenorphine. Rectal pH was measured with pH paper. Results Upon pharmacokinetic non-compartment analysis of high-dose buprenorphine (0.1 mg/kg), average maximal plasma concentration was found to be 1.13 ng/ml, time to maximal plasma concentration was 45 mins and area under the plasma concentration–time curve was 94.19 ng*min/ml, representing low but potential bioavailability. Mean residual time was 152.2 mins and the half-life was 92.6 mins. A wide range of plasma concentrations within the cohort was measured and two of the cats had to be excluded from statistical analysis owing to incomplete uptake. Vital parameters of all cats were considered to be normal but three of the cats showed mydriasis up to 8 h after application. After the administration of a low-dose suppository or a rectal gel (0.02 mg/kg) within pilot studies, no buprenorphine was detected in cat plasma. Rectal pH in all cats was between 7.7 and 8. Conclusions and relevance The rectal application of buprenorphine at a dose of 0.1 mg/kg revealed a potential but weak uptake in cats. Regarding effective concentrations in previous pharmacokinetic investigations, rectal administration is currently not recommended for good provision of opioid analgesia in cats. Pharmacological investigations of formulation and galenics in order to improve the rectal bioavailability of buprenorphine remain to be clarified before further dose-finding and pharmacokinetic/pharmacodynamic studies are performed.

Ceftriaxone Absorption Enhancement for Noninvasive Administration as an Alternative to Injectable Solutions

ABSTRACT Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop noninjectable formulations that can reduce treatment delays in resource-limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via nonparenteral administration. This article presents all available data on the nonparenteral absorption of ceftriaxone in humans and animals, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new data from preclinical studies with rabbits, and discusses the importance of these data for the development of noninjectable formulations for noninvasive treatment. The combined results indicate that the rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, chenodeoxycholate sodium salt (Na-CDC), used as an absorption enhancer at a 125-mg dose, together with a 500-mg dose of ceftriaxone provided 24% rectal absorption of ceftriaxone and a maximal plasma concentration of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for the bioavailability of other formulations before assessment in humans.

Absorption and Elimination of Oat Avenanthramides in Humans after Acute Consumption of Oat Cookies

Background. Avenanthramides (AVA) are a group of diphenolic acids found only in oats that have anti-inflammatory and antioxidant effects. Absorption of AVAs in humans after oral consumption of natural oat flour is unknown.Objective. To examine the appearance of AVAs in plasma after oral ingestion of oat cookies and estimate key pharmacokinetic parameters.Methods. Male and female nonobese participants (n=16) consumed three cookies made with oat flour containing high (229.6 mg/kg, H-AVA) or low (32.7 mg/kg, L-AVA) amounts of AVAs, including AVA-A, AVA-B, and AVA-C. Blood samples were collected at 0, 0.5, 1, 2, 3, 5, and 10 h after ingestion. Plasma total (conjugated and free) AVA concentrations were quantified using UPLC-MS, and pharmacokinetic parameters for each AVA were estimated.Results. AVAs reached peak concentrations in plasma between 2 and 3 h for the H-AVA group and between 1 and 2 h for the L-AVA group. Maximal plasma concentrations for AVAs were higher in the H-AVA than in the L-AVA group. AVA-B demonstrated a longer half-life and slower elimination rate than AVA-A and AVA-C.Conclusions. AVAs found naturally in oats are absorbed in the plasma after oral administration in humans. AVA-B has the slowest elimination rate and the longest half-life compared to AVA-A and AVA-C, while AVA-C demonstrated the lowest plasma concentrations. This study is registered with ClinicalTrials.gov identifierNCT02415374.

Preparation and in vivo evaluation of a gel-based nasal delivery system for risperidone

The aim of this study was to prepare a nasal gel of risperidone and to investigate the pharmacokinetics and relative bioavailability of the drug in rats. Compared with oral dosing, the risperidone nasal gel exhibited very fast absorption and high bioavailability. Maximal plasma concentration (cmax) and the time to reach cmax (tmax) were 15.2 μg mL-1 and 5 min for the nasal gel, 3.6 μg mL-1 and 30 min for the oral drug suspension, respectively. Pharmacokinetic parameters such as tmax′, cmax and AUC of oral and nasal routes were significantly different (p < 0.01). Relative bioavailability of the drug nasal preparation to the oral suspension was up to 1600.0 %. Further, the in vitro effect of the risperidone nasal gel on nasal mucociliary movement was also investigated using a toad palate model. The risperidone nasal formulation showed mild ciliotoxicity, but the adverse effect was temporary and reversible.

Bioavailability and pharmacokinetics of cefotaxime in Muscovy ducks

The pharmacokinetic profile of cefotaxime following a single intravenous (IV) and intramuscular (IM) injection was studied in Muscovy ducks. Cefotaxime was given at a dose rate of 25 mg/kg b.wt. for both routes. After IV injection, the plasma levels of cefotaxime estimated at 0.08 h was 70.87 μg/ml, which declined gradually and cefotaxime was detected up to 10 h (0.59 μg/ml). The mean values of CL, Vdss and t1/2β of cefotaxime in muscovy ducks were 0.22 l/kg/h, 0.51 l/kg and 1.81 h, respectively. After IM injection, maximum plasma concentration (Cmax) was (14.72 μg/ml), time of maximal plasma concentration (tmax) was (2.3 h) and elimination half-life (t1/2el)was (1.77 h). Bioavailability following IM injection was 79.61%, and in vitro protein binding percent was 31.48%. A recommended IM dosage for cefotaxime in muscovy ducks would be 30 mg/kg b.wt., repeated at 12 h intervals will provide a therapeutic plasma concentrations exceeding the MIC≤0.5 µg/ml for most susceptible pathogens in ducks.