Influence of Type and Level of Water-Soluble Additives on Drug Release and Surface and Mechanical Properties of Surelease® Films

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.     

Toxicology and Genetic Susceptibility of Drugs and Pollutant

S21Possibleinvolvementofhereditaryfactors intheriskmodulationofarseniasisintwoethnic clansexposedtoindoorcombustionofhigharse niccoal LINGuo Fang1,DUHui2,CHENJi Gang3,LU Hong Chao2,GUOWei Chao1,ZHANGXin Jiang4,SHENJian Hua1(1.ShanghaiInstituteforBiologicalSciences,Institute ofPlantPhysiologyandEcology,ChineseAcademyof Sciences,Shanghai200032,China;2.Prefecture CenterforDiseasePreventionandControl,Guiyang562400,China;3.MunicipalCenterforDiseasePre ventionandControl,Shang…     

Bioavailability of β-acetyldigoxin after single and repeated doses of tablets and solution

Summary In eight healthy volunteers the bioavailability of -acetyldigoxin solution and tablets was measured after single and multiple doses. Plasma and urine data were used to calculate bioavailability by four different methods. The differences obtained and the interindividual variations suggested that different and independent methods should be employed to assess absolute and true bioavailability. There was no significant difference between the regimens and both preparations had similar bioavailability; mean values (± SD) for the solution were 68.3 ± 8.7 % (single dose) and 68.6±5.9 % (multiple doses), and for the tablets 72.8±7.5 % and 66.1±6.0 %, respectively. For routine measurements, single dose studies with plasma and urine sampling for 24 hours and 48 hours, respectively, were an accurate and practicable procedure.     

Pharmacology and Toxicology of Herbs

S11StudiesontoxicityofChinesemedicines anddecreasedvirulencethroughthecompatibili tyofherbalingredients LIPeng Tao(CST)(BeijingUniversityofTraditionalChineseMedicine,Beijing100029,China)Beginningfromthereportoftherenalinjuryin ducedbyaristolochicacid,thepoisonoussideeffects ofChinesemedicineshaveattractedmoreandmoreat tentions,whichhaveproducedhugeinfluenceontheprogressoftraditionalChinesemedicines.Itbecomesa vitallyimportantissuetounderstandanduseChinese medicinescorrectly.Thetoxicity…     

Pharmacokinetics and Pharmacodynamics of Nitrendipine

ＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓａｎｄＰｈａｒｍａｃｏｄｙｎａｍｉｃｓｏｆＮｉｔｒｅｎｄｉｐｉｎｅＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓａｎｄＰｈａｒｍａｃｏｄｙｎａｍｉｃｓｏｆＮｉｔｒｅｎｄｉｐｉｎｅＭａｒｓｔｅｒ＇ｓＤｅｇｒｅｅＺｈｅｎ－ＬｉＬｉｎＳｕ...     

Synthesis of β-amino carbonyl derivatives of coumarin and benzofuran and evaluation of their biological activity

A series of β-amino carbonyl compounds containing coumarin (4a–h) and benzofuran (6a–i) moieties was synthesized by a three component Mannich reaction of 3-acetyl-2H-chromen-2-one (1) or 1-(1-benzofuran-2-yl) ethanone (5) with p-substituted aromatic aldehydes (2a–g) and aromatic amines (3a–b) in the presence of cerric ammonium nitrate as a catalyst. The newly synthesized compounds were screened for antimicrobial and antioxidant activities. Compounds 4b, 4e, 4f, 6f, 6g, and 6i showed microbial inhibition with minimal inhibition concentration ranging between 0.040 and 0.500 mg/mL, compounds 4b, 4c, 6c, 6e, and 6i showed promising free radical scavenging activity and compounds 4b, 4f, 6c, 6d, and 6h showed good chelating ability with Fe²⁺ ions. The synthesized compounds were studied for docking on the enzyme, glucosamine-6-phosphate synthase to predict the binding affinity and orientation at the active site of the receptor.     

Transdermal Penetration of Vasoconstrictors—Present Understanding and Assessment of the Human Epidermal Flux and Retention of Free Bases and Ion-Pairs

Purpose. As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA). Methods. We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol:water (1:1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1:1 molar ratio ion-pairs with SA in liquid paraffin. Results. As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 ± 11.7 g/cm²/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 ± 2.3 and 12.0 ± 1.6 g/cm²/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 ± 0.6, 7.8 ± 0.8 and 1.1 ± 0.1 respectively. Transdermal transport of VC's is discussed. Conclusions. Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by individual solute characteristics.     

Synthesis and SAR of Benzisothiazole- and Indolizine-β-d-glucopyranoside Inhibitors of SGLT2

d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure−activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC₅₀ of 10 nM.     

Pharmacokinetics of zimelidine in humans — Plasma levels and urinary excretion of zimelidine and norzimelidine after intravenous and oral administration of zimelidine

Summary Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 h±1.3 SD) or intravenous dosing (5.1 h±0.7 SD). An average of 50% of the ingested oral dose reached the systemic circulation. Excretion of unchanged zimelidine in urine was on average 1.26% of the intravenous dose. In appears that zimelidine is completely absorbed from the gastrointestinal tract and first-pass metabolism in the liver reduces the bioavailability to 50%. The mean plasma half-life for norzimelidine was 22.8 h. The area under the plasma concentration time curve for norzimelidine after oral administration was 92% of that after intravenous administration. The plasma concentration of both zimelidine and norzimelidine are predicted to approach steady-state within 3–5 days.     

Immunotoxicity and Neurotoxicity of Pharmaceuticals and Environmental Toxic Substances

W31ICHS8Guideline:immunotoxicitystud iesforhumanpharmaceuticals JSAWADA(NationalInstituteofHealthSciences,Tokyo,Japan)Toxicitytotheimmunesystemencompassessup pressionorenhancementoftheimmuneresponse.Sup pressionoftheimmuneresponsecanleadtodecreased hostresistancetoinfectiousagentsortumorcells.En hancingtheimmuneresponsecanexaggerateautoim munediseasesorhypersensitivity.Therfore,evaluationofpotentialadverseeffectsofhumanpharmaceuticals ontheimmunesystemshouldbeincorporatedinto standardd…     

Risk–benefit of antiemetics in prevention and treatment of chemotherapy-induced nausea and vomiting

The development of effective antiemetic prophylaxis is one of the most significant steps forward in the area of supportive care. Fifteen years ago, patients receiving chemotherapy had to face the fact that nausea and vomiting were inevitable adverse effects, which could only be partially prevented by treatment with antiemetics such as dopamine (DA) D2 receptor antagonists and corticosteroids. The first group of drugs specifically developed as antiemetics was the serotonin (5-hydroxytryptamine [5-HT]₃) receptor antagonists. These drugs have dramatically improved prophylaxis of chemotherapy-induced emesis, particularly when used in combination with a corticosteroid. This combination has resulted in a significant decrease in the number of patients vomiting, whereas the improvement in the prophylaxis of nausea has been less successful. Another group of antiemetics, the neurokinin (NK)₁ receptor antagonists, has recently been developed, and the first drug in this class, aprepitant, has been approved by the FDA and the EU authorities. Studies have showed that patients benefit from the use of this drug in combination with standard antiemetic therapy (5-HT₃ receptor antagonist plus a corticosteroid), both in the acute and delayed phase of nausea and vomiting induced by cisplatin-based chemotherapy. This development has not only led to improved efficacy but also to a decreased risk associated with the use of antiemetics. One of the problems with traditional antiemetics, for example, the DA D2 receptor antagonists, is the risk of unpleasant adverse effects including restlessness and dystonic reactions. To avoid these adverse effects, combination with benzodiazepines or antihistamines was necessary, often resulting in sedation. Modern research also includes pharmacogenomic investigations. This has led to speculation about the importance of drug–drug interactions involving antiemetics through competition for metabolism by the cytochrome P450 isoenzymes. The worst possible interaction would be a decrease in the effect of different cytotoxins but there is no evidence that such interactions are of importance in daily clinical practice. Guidelines are useful tools in the optimisation of antiemetic prophylaxis but, unfortunately, implementation of the evidence-based recommendations is far from successful. A prerequisite for further optimisation of antiemetic prophylaxis is updating of the guidelines, including recommendations for the use of NK₁ receptor antagonists (aprepitant), followed by implementation of these recommendations in the clinic. Future research must include ‘the difficult trials’ focusing on the remaining groups of patients with severe chemotherapy-induced nausea and vomiting, including patients with refractory and breakthrough emesis.     

Synthesis and Study of the Analgesic and Antiinflammatory Activity of α-Acetoxyphenylacetic Acid Amides

Pharmaceutical Chemistry Journal -     

Review of synthesis, assay, and prediction of β and γ-secretase inhibitors

Alzheimer's disease (AD) is characterize with several pathologies this disease, amyloid plaques, composed of the β-amyloid peptide and β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised Desing, synthesis, and Biological assay of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compound to find out the structural requirements. Next, we revised QSAR studies using method of Artificial Neural Network (ANN) in order to understand the essential structural requirement for binding with receptor for β and γ-secretase inhibitors.     

Self-Assembly of α-Cyclodextrin and β-Cyclodextrin: Identification and Development of Analytical Techniques

Recently, it has been shown that cyclodextrins (CDs) self-assemble in aqueous solutions to form aggregates. Such aggregation can give rise to formation of particulate matter in aqueous solutions. However, the analytical methodology available to detect and quantify these aggregates is still quite inadequate. Here, 5 different methods for evaluation of CD aggregate formation and determination of the critical aggregation concentration are evaluated: osmometry, viscosity, surface tension, dynamic light scattering, and permeability studies. Both the viscosity and surface tension methods applied were inadequate for aggregate detection, whereas the osmometry method can be used to study CD aggregation but with some limitations. Dynamic light scattering has also some limitations although it can be applied to detect CD aggregates and to estimate their hydrodynamic diameter. Overall, permeation studies proved to be the best method to detect and determine critical aggregation concentration. These results suggested that β-cyclodextrin (βCD) has higher tendency to aggregate than α-cyclodextrin (αCD). Filtration of αCD and βCD solutions affected the aggregate size distribution by breaking larger aggregates in to smaller ones that then reassembled to regenerate the larger ones upon storage. The osmolality studies showed that in aqueous αCD and βCD solutions, solute-solute interactions are favored over solute-solvent interactions with consequent CD aggregate formation.     

Different roles of PKC and PKA in effect of interferon-y on proliferation and collagen synthesis of fibroblasts

AIM: To study the signal roles of protein kinase C (PKC) and protein kinase A (PKA) in the influence of interferon-γ(IFN-γ) on proliferation and collagen synthesis of flbroblasts derived from hypertrophic scar (HS-FB) and normal skin (NS-FB). METHODS: HS-FB and NS-FB were cultured and passaged in Dulbecco's modified Eagle's medium (DMEM). Activity of PKC and PKA were assayed by transferring phosphorus (32P) into substrate after treatment with IFN-γ1000 kU/L at 10, 30, 60, and 120 min. Cell proliferation was determined with MTT assay. The collagen synthesis was measured with [3H]proline incorporation and Type Ⅲ pre-collagen was determined with radioimmunoassay. RESULTS: After exposure to IFN-γ1000 kU/L for 30 min, PKC activity of HS-FB and NS-FB increased from 2.57±0.14 and 2.13±0.12 nmol·min-1·g-1 of control to 3.75±0.19 and 3.36±0.16 nmol·min-1·g-1 respectively (P<0.05). After exposure to IFN-y 1000 kU/L for 60 and 120 min, PKA activities of HS-FB increased gradually from 0.82±0.04 nmol·m     

Effect of yeast and potassium oxonate on formation and excretion of uric acid and renal function of SD rats北大核心CSCD

OBJECTIVE: To investigate the effect of potassium oxonate and yeast on formation and excretion of uric acid (UA) and renal function in rats, and to describe the characteristics of hyperuricemia in rats induced by potassium oxonate and yeast. METHODS: SD rats were given yeast 21 g·kg-1 and potassium oxonate 100, 200 and 300 mg·kg-1, respectively, once a day for 35 d. Levels of UA, creatinine (CRE), urea nitrogen (BUN) and the activity of adenosine deaminase (ADA), xanthine oxidase (XOD), guanine deaminase (GuDa) in serum were determined on the 14th 28th and 35th day, respectively. Levels of UA, CRE, BUN, protein in urine, urine specific gravity and urine volume were determined on the 28th day while UA excretion and clearance were counted. These rats were sacrificed on the 35th day to weigh the right kidney and calculate the kidney index. RESULTS: Compared with normal control group, serum UA levels of three treatment groups were significantly higher from the 14th to the 35th day(P<0.01); CRE levels of three treatment groups were significantly higher on the 35th day(P<0.05, P<0.01); ADA activity was significantly lower in the groups of yeast 21 g·kg-1 and potassium oxonate 100 and 300 mg·kg-1 on the 14th day (P<0.01) and in the group of yeast 21 g · kg-1 and potassium oxonate 200 mg · kg-1 on the 14th to 28th day (P<0.05); XOD activity of the groups of yeast 21 g · kg-1 and potassium oxonate 300 mg · kg-1 was significantly higher on the 14th to 28th day (P<0.05, P<0.01); UA excretion and clearance of three treatment groups were significantly lower on the 28th day (P<0.05, P<0.01); the kidney index of the three treatment groups was significantly higher on the 35th day (P<0.01). CONCLUSION: Yeast and potassium oxonate can elevate levels of UA in rats, which may be related to the changes of XOD and ADA activity and the disturbance of UA excretion that is likely associated with kidney damage.     

Plasma concentration of α-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester

Summary The plasma concentrations of free -methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following -methyldopa (1 g) orally. Five of these patients subsequently received -methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of -methyldopa intravenously. After oral administration a large amount of total plasma -methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated -methyldopa in plasma (ratio at 4 hours ranged from 3.73 – 0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous -methyldopa than -methyldopate. The plasma concentration of -methyldopa (free and esterified) 60 minutes after i.v. -methyldopate was 1.7±0.3 µg/ml wile at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 µg/ml. Although small amounts of sulphate conjugate were detected after i.v. -methyldopate, insignificant quantities of conjugate were found after i.v. -methyldopa. The average fall in mean arterial pressure was 27 mm Hg following i.v. -methyldopa but only 2.7 mm Hg following -methyldopate. These results suggest that sulphate conjugation of -methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of -methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free -methyldopa have been demonstrated.     

The ethics and practice of authorship and peer review

Ｏｎｃｅａｃｌｉｎｉｃａｌｔｒｉａｌｉｓｃｏｍｐｌｅｔｅｄ，ｉｔｍｕｓｔｂｅｐｕｂｌｉｓｈｅｄｉｎｏｒｄｅｒｆｏｒｏｔｈｅｒｓｔｏｋｎｏｗｏｆｉｔｓｒｅｓｕｌｔｓ．Ｐｒｉｍａｒｙｓｏｕｒｃｅ，ｐｅｒｒｅｖｉｅｗｅｄｍｅｄｉｃａｌｊｏｕｒｎａｌｓａｒ...     

Different roles of PKC and PKA in effect of interferon-γ on proliferation and collagen synthesis of fibroblasts

AIM: To study the signal roles of protein kinase C (PKC) and protein kinase A (PKA) in the influence of interferon-gamma (IFN-gamma) on proliferation and collagen synthesis of fibroblasts derived from hypertrophic scar (HS-FB) and normal skin (NS-FB). METHODS: HS-FB and NS-FB were cultured and passaged in Dulbecco modified Eagles medium (DMEM). Activity of PKC and PKA were assayed by transferring phosphorus (32P) into substrate after treatment with IFN-gamma 1000 kU/L at 10, 30, 60, and 120 min. Cell proliferation was determined with MTT assay. The collagen synthesis was measured with [3H]proline incorporation and Type III pre-collagen was determined with radioimmunoassay. RESULTS: After exposure to IFN-gamma 1000 kU/L for 30 min, PKC activity of HS-FB and NS-FB increased from 2.57 +/- 0.14 and 2.13 +/- 0.12 nmol x min(-1) x g(-1) of control to 3.75 +/- 0.19 and 3.36 +/- 0.16 nmol x min(-1) x g(-1), respectively (P < 0.05). After exposure to IFN-gamma 1000 kU/L for 60 and 120 min, PKA activities of HS-FB increased gradually from 0.82 +/- 0.04 nmol x min(-1) x g(-1) of control to 1.03 +/- 0.05 and 1.23 +/- 0.06 nmol x min(-1) x g(-1), respectively (P<0.05). The PKA activities of NS-FB also increased from 0.52 +/- 0.03 nmol x min(-1) x g(-1) of control to 0.68 +/- 0.03 and 0.89 +/- 0.05 nmol x min(-1) x g(-1), respectively (P<0.05). The proliferation and collagen synthesis were enhanced by PKC activator (containing phosphatidylserine, diacylglycerol and Ca2+) and PKA inhibitor [H(7)250 micromol/L, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine], and inhibited by PKC inhibitor (GF109 250 micromol/L) and PKA activator (cAMP 25 micromol/L) (P<0.01). GF109 abrogated increased proliferation and collagen synthesis by IFN-gamma but it did not affect the inhibitory effects of IFN-gamma. At 120 min H7 reversed the inhibitory functions of IFN-gamma. CONCLUSION: IFN-gamma transiently increased proliferation and collagen synthesis of HS-FB and NS-FB by activation of PKC and subsequently inhibited proliferation and collagen synthesis by activation of PKA.     

Pharmacology and Toxicology of Major Constituents of Marijuana—On the Metabolic Activation of Cannabinoids and Its Mechanism

Many oxidative metabolites of tetrahydrocannabinols (THCs), active components of Cannabis sativa L. (Cannabinaceae), were pharmacologically potent, and 11‐hydroxy‐THCs, 11‐oxo‐Δ⁸‐THC, 7‐oxo‐Δ⁸‐THC, 8β,9β‐epoxyhexahydrocannabinol (EHHC), 9α,10α‐EHHC and 3'‐hydroxy‐Δ⁹‐THC were more active than THC in pharmacological effects such as catalepsy, hypothermia and barbiturate synergism in mice, indicating that these metabolites are active metabolites of THCs. Cannabidiol (CBD), another major component, was biotransfomred to two novel metabolites, 6‐hydroxymethyl‐Δ⁹‐THC and 3‐pentyl‐6, 7, 7a, 8, 9, 11a‐hexahydro‐1, 7‐dihydroxy‐7,10‐dimethyldibenzo[b,d]oxepin (PHDO) through 8R,9‐epoxy‐CBD and 8S, 9‐epoxy‐CBD as intermediates, respectively, identified by us. Both metabolites have some pharmacological effects comparable to Δ⁹‐THC. Cannabinol (CBN), the other major component, was mainly metabolized to 11‐hydroxy‐CBN by hepatic microsomes of animals including humans. The pharmacological effects of the metabolite were higher than those of CBN demonstrating that 11‐hydroxylation of CBN is an activation pathway of the cannabinoid as is the case in THCs. Tolerance developed to catalepsy, hypothermia and pentobarbital‐induced sleep prolonging effects of Δ⁸‐THC and its active metabolite, 11‐hydroxy‐Δ⁸‐THC. Reciprocal cross‐tolerance also developed to pharmacological effects and the magnitude of tolerance development produced by the metabolite was significantly higher than that by Δ⁸‐THC indicating that 11‐hydroxy‐Δ⁸‐THC has important role not only in the pharmacological effects but also its tolerance development of Δ⁸‐THC. THCs and their metabolites competed with the specific binding of CP‐55,940, an agonist of cannabinoid receptor, to synaptic membrane from bovine cerebral cortex. The Ki value of THCs and their metabolites were closely parallel to their pharmacological effects in mice. A novel cytochrome P450 (cyp2c29) was purified and identified for the first time by us as a major enzyme responsible for the metabolic activation of Δ⁸‐THC at the 11‐position in the mouse liver. cDNA of cyp2c29 was cloned from a mouse cDNA library and its sequence was determined. All of major P450s involving the metabolic activation of Δ⁸‐THC at the 11‐position are belonging to CYP2C subfamily in mammalian liver.