• Journal of Pharmaceutical Investigation
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• v.22 no.2
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• pp.77-96
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• 1992

In recent years intranasal administration of drugs has received great attention as a convenient and efficent method of drug delivery because of its potential to improve the systemic effect of substances with a poor oral bioavailability. In addition to offering advantages such as rapid absorption, fast onset of action and avoiding the first -pass effect, it provides for delivery of drugs from very lipophilic drugs such as steroids to polar and hydrophilic drugs such as peptides and proteins. However, little is still known about the nature of various barriers existing in the nasal mucosae as well as mechanism by which these molecules are absorbed. This review article therefore intends to discuss nasal physiology, experimental methods and evaluation of absorption from the nasal cavity, factors influencing nasal absorption, mechanism of nasal absorption, approaches to improve the residence time and to obtain the sustained-release effect of intranasally administered drugs, promoters and mechanism for the enhancement of nasal absorption, Several examples for intranasal delivery of various systemically effective drugs will be reviewed and illustrated. Drug metabolism in the nasal mucosae and problems associated with intranasal administration of drugs will be also discussed.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.205-212
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• 2001

Background : The information on nasal transport and the metabolism of peptides have been obtained from pharmacokinetic investigations in experimental animals. However, there are no transport and metabolic studies of human nasal epithelial cells. In this study, the permeability characteristics and the metabolic properties of in vitro human nasal cell monolayers were investigated. Material and Methods : Normal human inferior nasal conchal tissue samples were obtained from patients undergoing endoscopic nasal cavitary surgery. The specimens were cultured in a transwell using an air-liquid Interface (ALI) culture, and the transepithelial electrical resistance (TEER) value of the blank filter and confluent cell monolayers were measured. To determine the % leakage of mannitol, $4{\mu}mol%$ $^{14}C$-labelled mannitol was added and the % leakage was measured every 10 minute for 1 hour. Result : Human nasal epithelial cells in the primary culture grew to a confluent monolayer within 7 days and expressed microvilli. The tight junction between the cells was confirmed by transmission electron microscopy. The TEER value of the blank filter, fifth day and seventh day reached $108.5\;ohm.cm^2$, $141\;ohm.cm^2$ and $177.5\;ohm.cm^2$, respectively. Transcellular % leakage of the $^{14}$-mannitol at 10, 20, 30, 40, 50 and 60 minutes was $35.67{\pm}5.43$, $34.42{\pm}5.60$, $32.75{\pm}5.71$, $31.76{\pm}4.22$, $30.96{\pm}3.49$ and $29.60{\pm}3.68\;%$, respectively. Conclusion : The human nasal epithelial monolayer using ALI culture techniques is suitable for a transcellular permeability study. The data suggests that human nasal epithelial cells In an ALI culture technique shows some promise for a nasal transport and metabolism study.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.71-71
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• 1993

Carboxylesterase is widely distributed in the tissues of vertebrates, insects, plants and mycobacteria. Among various tissues of animals and humans, the highest esterase activity with various substrates is found in the liver. Kidney has moderate carboxylesterase activity in the proximal tubules. Considerable esterase activity is also found in the small intestine epithet elial cells and serum of mammals. Besides these tissues, carboxylesterase has been found in the lung, testis, adipose tissue, nasal mucosa and even in the central nervous system. Hepatic microsomal carboxylesterase catalyzes the hydrolysis of a wide variety of endogenous and exogenous compounds such as carboxylester, thioester and aromatic amide. Since carboxylesterases are important for metabolic activation of prodrugs and detoxification of xenobiotics, differences in substrate specificity and immunological properties of this enzyme are important in connection with choosing a suitable laboratory animal for the evaluation of biotransformation and toxicity of drugs. On the other hand, liver, kidney, intestine and serum were found to contain multiple forms of carboxylesterases in animal species and humans. In fact, we have purified more than fifteen isoforms of carboxylesterases from microsomes of liver, kidney and intestinal mucosa of nine animal species and humans. and characteristics of these isoforms were compared each other in terms of their physical and immunochemical properties. On the other hand, we have reported that hepatic microsomal carboxylesterases are induced by many exogenous compounds such as phenobarbital, polycyclic aromatic hydrocarbons, Aroclor 1254, aminopyrine and clofibrate. Later, we showed that some isoforms of hepatic carboxylesterase were induced by glucocorticoids such as dexamethasone and 16 ${\alpha}$-carbonitrile, but other isoforms were rather inhibited by these compounds. These findings indicate that involvement of carboxylesterases in the metabolism and toxicity of drugs should be explained by the isoforms involved. Since 1991, we have carried out detailed research investigating the types of carboxylesterases involved in the metabolic activation of CPT-11, a derivative of camptothecin, to the active metabolite, SN-38. The results obtained strongly suggest that some isoforms of carboxylesterase of liver microsomes and intestinal mucosal membrane are exclusively involved in CPT-11 metabolism. In this symposium, the properties of carboxylesterase isoforms purified from liver, kidney and intestine of animal species and humans are outlined. In addition, metabolism of CPT-11, a novel antitumor agent, by carboxylesterases in relation to the effectiveness will also be discussed.

• YAKHAK HOEJI
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• v.38 no.1
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• pp.67-77
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• 1994

In order to investigate the feasibility of transmucosal delivery of the model peptide, LHRH, metabolism of LHRH and inhibition effect of medium chain fatty acid salts were studied in rabbit mucosal homogenate. LHRH incubated in homogenates of rectal(RE), nasal(NA) and vaginal(VA) mucosa were assayed by HPLC. Five to six degradation products of LHRH were deterted and the degradation of LHRH$(500\;{\mu}g/ml)$ followed the first order kinetics. The main degradation products were found as $LHRH^{1-5}(M-I)$, $LHRH^{1-3}(M-II)$ and $LHRH^{1-6}(M-III)$ by the method of amino acid analysis. The half-lives of LHRH in the mucosal homogenates were found to be less than 20 min at protein concentration of 2.5 mg/ml with the order of VA>NA>RE mucosal homogenate. Medium chain fatty acid salts such as sodium caprylate $(C_8)$, sodium caprate $(C_{10})$ and sodium laurate $(C_{12})$ at the concentration of $0.5%{\sim}1.0%$ inhibit the proteolysis of LHRH significantly. The addition of sodium laurate(0.5%) into the NA and VA mucosal homogenates protected LHRH completely from the degradation.

• Journal of Pharmaceutical Investigation
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• v.27 no.1
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• pp.15-22
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• 1997

The mucosal route of administration(nasal, buccal, conjunctival and vaginal) has recently been considered as an alternative to parenteral delivery for many peptide drugs because enzymatic degradation of these agents may be partly avoided. The objective of these study was to establish the optimal mucosal administration dosage form of $LHRH/[D-Ala^6]LHRH$, based on presystemic metabolism. We reported previously the peptidase inhibition effect of medium chain fatty acid salts(sodium caprylate, soadium caprate and sodium laurate), EDTA and STDHF on the proteolysis of $LHRH/[D-Ala^6]LHRH$ in rabbit mucosal homgenates. We also reported that EDTA, STDHF and sodium laurate markedly increased the potency of $LHRH/[D-Ala^6]LHRH$ solution applied vaginally. In the present study, by administration of polycarbophil hydrogel containing LHRH the ovulation inducing activity was 3.3 times greater than solution. These results indicate not only peptidase inhibitor but also polycarbophil hydrogel significantly improved the absorption of this drug. The results of this study would provide the feasibility as a rational dosage form for improving bioavailability and self administration of this hydrogel by the vaginal application.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.179-182
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• 2013

Human cytochrome P4502E1 (CYP2E1) is a well-conserved xenobiotic-metabolizing enzyme expressed in liver, kidney, nasal mucosa, brain, lung, and other tissues. CYP2E1 is inducible by ethanol, acetone, and other low-molecular weight substrates and may mediate development of chemically-mediated cancers. CYP2E1 polymorphisms alter the transcriptional activity of the gene. This study was conducted in order to investigate the allele frequency variation in different populations of Andhra Pradesh. Two hundred and twelve subjects belonging to six populations were studied. Genotype and allele frequency were assessed through TaqMan allelic discrimination (rs6413419) and polymerase chain reaction-sequencing (-1295G>C and -1055C>T) after DNA isolation from peripheral leukocytes. The data were compared with other available world populations. The SNP rs6413419 is monomorphic in the present study, -1295G>C and -1055C>T are less polymorphic and followed Hardy-Weinberg equilibrium in all the populations studied. The -1295G>C and -1055C>T frequencies were similar and acted as surrogates in all the populations. Analysis of HapMap populations data revealed no significant LD between these markers in all the populations. Low frequency of $CYP2E1^*c2$ could be useful in the understanding of south Indian population gene composition, alcohol metabolism, and alcoholic liver disease development. However, screening of additional populations and further association studies are necessary. The heterogeneity of Indian population as evidenced by the different distribution of $CYP2E1^*c2$ may help in understanding the population genetic and evolutionary aspects of this gene.

• Toxicological Research
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• v.24 no.3
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• pp.201-206
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• 2008

Exposure to formaldehyde(FA) is closely associated with adverse health effects such as irritation, inflammation, and squamous cell carcinomas of the nasal cavities. Owing to its rapid metabolism and elimination, exposure to FA does not always result in an increased concentration in blood or urine of animals and humans. Therefore, the development of biomarkers for FA exposure is necessary for risk assessment. In the present study, the effects of FA were investigated on the expression of genes involved in the MAPK pathway in vitro and results confirmed in rats exposed to FA by inhalation. Treatment of Hs 680.Tr human tracheal epithelial cells with FA induced gene expression for PDGFA, TNFSF11, SHC1, and HRAS. HRAS expression was also increased in tracheas of rats exposed to FA. In addition, FA exposure induced the expression of RASSF4, a member of the Rasassociation domain family of Ras effectors, in rat tracheas. In conclusion, data showed FA-inducible expression of genes involved in the MAPK pathway occurred and increased expression of HRAS and RASSF4 was noted in rat tracheas subchronically exposed to FA by inhalation. These genes may serve as molecular targets of FA toxicity facilitating the understanding of the toxic mechanism.