Clinical Pharmacology

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This division was known as Pharmacology until 27 June 2013.

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Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy
(Stellenbosch : Stellenbosch University, 2015-12) Flepisi, Thabile Brian; Rosenkranz, Bernd; Bouic, Patrick J. D.; Sissolak, Gerhard; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
ENGLISH ABSTRACT: INTRODUCTION: Altered immune mechanisms play a critical role in the pathogenesis of Non-Hodgkin lymphoma (NHL), as evidenced by increased rates of NHL among HIV+ patients [De Roos et al., 2012; Mellgren et al., 2012]. AIMS: To determine whether biomarkers of B-, T-cell activation, and inflammation are elevated in HIV+NHL patients; and whether cART influences their expression. METHODS: The expression of CD8+CD38 and FoxP3 were determined by flow cytometry; the serum concentrations of circulating sCD20, sCD23, sCD27, sCD30 and sCD44 were determined by enzyme linked immunosorbent assay (ELISA); and the serum concentrations of circulating IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α were determined by meso-scale discovery (MSD) assay in 141 participants consisting of HIV positive NHL (HIV+NHL), HIV negative NHL (NHL); combination antiretroviral treated HIV+ (HIV+ cART), treatment naive HIV+ (cART-naïve HIV+) patients; and healthy controls. RESULTS: HIV+NHL patients had higher serum concentrations of sCD20 (p<0.0001 and p=0.0359), sCD23 (p=0.0192 and p<0.0001), sCD30 (p=0.0052 and p<0.0001), sCD44 (p=0.0014 and p<0.0001), and IL-4 (p=0.0234 and p=0.03360); and lower expression of FoxP3 (p<0.0001 and p=0.0171) as compared to NHL and HIV+ cART patients. As compared to NHL patients, the serum concentrations of IL-2 (p=0.0115), and TNF-α (p=0.0258) were higher in HIV+NHL patients, while those of IL-1β (p=0.0039) were significantly lower. HIV+NHL patients had higher expression of CD8+CD38 (p=0.0104), serum concentrations of IFN-γ (p=0.0085), and IL-6 (p=0.0265); and lower serum concentrations of IL-12p70 (p=0.0012) than HIV+ cART patients. As compared to controls, NHL had higher concentrationsof all biomarkers investigated except FoxP3 expression. As compared to HIV+ cART and controls, cART-naïve HIV+ patients had higher concentrations of all biomarkers investigated except sCD23 and FoxP3 expression. CONCLUSION: Biomarkers of chronic B- and T-cell activation and inflammation are up-regulated in HIV+NHL and the untreated HIV+ state. cART decreases immune activation and inflammation.
In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential
(Stellenbosch : Stellenbosch University, 2013-12) Fasinu, Pius Sedowhe; Rosenkranz, Bernd; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.
ENGLISH ABSTRACT: Introduction Earlier studies have shown the popularity of herbal products among people as traditional, complementary or alternative medication. One of the major clinical risks in the concomitant administration of herbal products and prescription medicine is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes and transport proteins. The aim of this study was to investigate the potential of the crude extracts of popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes and transport proteins through in vitro assessment. Methods Medicinal herbs were obtained from traditional medical practitioners and 15 were selected for this study. The selected herbal products were extracted and incubated with human liver microsomes to monitor the following reactions as markers for the metabolic activities of the respective CYP: phenacetin O-deethylation (CYP1A2), diclofenac 4‟-hydroxylation (CYP2C9), S-mephenytoin 4‟- hydroxylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In addition, the influence of Lessertia frutescens (formerly Sutherlandia frutescens) and Hypoxis hemerocallidea was investigated on more isozymes: coumarin 7-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), paclitaxel 6α-hydroxylation (CYP2C8), bufuralol 1‟-hydroxylation (CYP2D6), chlorzoxazone 6- hydroxylation (CYP2E1) and midazolam 1‟-hydroxylation (CYP3A4/5). The generation of the CYPspecific substrates/metabolites were monitored and quantified with the aid of LC-MS/MS. The metabolic clearance of midazolam using cryopreserved hepatocytes was monitored in the presence of Lessertia frutescens and Hypoxis hemerocallidea. The potential of both to inhibit human ATP-binding cassette (ABC) transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells overexpressing human breast cancer resistant protein (BCRP) and human P-glycoprotein (P-gp), respectively. Similarly, the potential for interactions with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) was assessed using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively. Results Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (methanolic extract), Hypoxis hemerocallidea, Spirostachys africana and Lessertia frutescens (aqueous extract), in ascending order of potency demonstrated strong inhibition of CYP1A2 activity (IC50 = 1-100 g/mL). Similarly, Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana and Pentanisia prunelloides inhibited CYP2C9 with IC50 less than 100 g/mL. The following demonstrated strong inhibition of CYP2C19 with IC50 values less than 100 g/mL: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens and Zantedeschia aethiopica. CYP3A4 was inhibited by Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria and Pentanisia prunelloides. Time-dependent (irreversible) inhibition of CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) and delay in the production of midazolam metabolites in the human hepatocytes, leading to a 40% decreased midazolam upscaled in vivo clearance, was observed with Lessertia frutescens. Further, Lessertia frutescence inhibited the activity of P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) and OATP1B3 (IC50 = 6.6 μg/mL). Hypoxis hemerocallidea inhibited the activity of OATP1B1 (IC50 = 118.7 μg/mL) and OATP1B3 (IC50 = 290.1 μg/mL) with no potent inhibitory effects on P-gp. None of the two inhibited the activity of BCRP within the tested concentrations. Conclusion The result indicates the potential for HDI between the selected medicinal herbs and the substrates of the enzymes investigated in this study, if sufficient in vivo concentrations are achieved.
Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach
(Stellenbosch : Stellenbosch University, 2016-03) White, Charlize; Rosenkranz, Bernd; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology.
ENGLISH ABSTRACT: INTRODUCTION Herbal products are popularly used as complementary and alternative medicines to treat a variety of conditions. Often patients use them in conjunction with conventional medicines. Herbal products contain many pharmacologically active phytochemicals that may interfere with the absorption, distribution, metabolism, and elimination of medicines. This interaction can lead to an increase of the plasma concentrations of other medicines to toxic levels, or to their decrease below therapeutic levels, resulting in lack of efficacy. The liver cytochrome P450 (CYP) enzymes are responsible for the metabolism of a large majority of medicines. In order to provide more information on the potential interaction between African herbal medicines and conventional medicines, the present study has investigated the inhibition of selected CYP enzymes by three popular South African medicinal plants, Buchu, African ginger, and Warburgia salutaris. METHODS Buchu capsules, African ginger, and Warburgia salutaris tablets were obtained in a local pharmacy. 60% methanol/water extracts were prepared and analysed by GC-MS to reveal the composition of the volatile components of each product. Fluorogenic inhibition assays were conducted using Vivid® recombinant CYP screening kits according to the manufacturer’s protocol. This protocol included the pre-incubation of herbal extracts, recombinant CYP isoform and cofactor solution. The metabolic reaction was initiated by the addition of CYP-specific substrate and NADP+; the solution was incubated for 30 minutes at 37°C, after which fluorescence was measured using a microplate reader. The percentage remaining activity was calculated and used to determine the IC50 values of each herbal product. Time - dependent inhibition (TDI) was evaluated using the normalized ratio, NADP+-, concentration -, and time - dependent approaches. RESULTS The GC-MS analysis revealed monoterpenes, sesquiterpenes, and alkane hydrocarbons in the volatile component. Warburgia salutaris, African ginger, and Buchu inhibited CYP2C19 with IC50 values of 5.88 μg/ml, 32.38 μg/ml, and 53.52 μg/ml, respectively. Likewise, the IC50 values of 5.64 μg/ml, 1.09 μg/ml, and > 100 μg/ml were obtained for inhibition of CYP3A4 by Warburgia salutaris, African ginger, and Buchu, respectively. Using the normalized ratio, Warburgia salutaris and African ginger showed time- and concentration - dependent inhibition of CYP1A2, and Buchu showed intermediate TDI effects that were not concentration dependent. All three extracts showed TDI of CYP3A4; the inhibition displayed by Buchu and Warburgia salutaris was NADP+ dependent. African ginger was the only extract to show NADP+ dependent inhibition of CYP1A2. A kinetic TDI assay Stellenbosch University https://scholar.sun.ac.za iii showed that the IC50 value of African ginger decreased over time, indicating TDI. Warburgia salutaris was not a time-dependent inhibitor of CYP3A4, and Buchu may have a limited time-dependent inhibitory effect. CONCLUSION Warburgia salutaris, African ginger, and Buchu have the potential to cause clinically relevant herb-drug interaction, if sufficient concentrations are achieved in vivo. Further studies are needed to confirm this finding.
Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS
(Stellenbosch : Stellenbosch University, 2015-03) Awortwe, Charles; Rosenkranz, Bernd; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology.
ENGLISH ABSTRACT: Introduction The increasing intake of traditional medicines among HIV/AIDS patients in sub-Saharan Africa needs urgent consideration by clinicians and other healthcare providers since the safety of such medications are unknown. The pharmacokinetic parameters - Absorption, Distribution, Metabolism and Elimination (ADME) play important role in the safety evaluation of drugs, thus implicating drug metabolizing enzymes and transporters as critical indicators for herb-drug interactions. The objective of this study was to evaluate the risk potential of seven herbal medicines commonly consumed by HIV/AIDS patients for drug interactions applying in vitro models. In this study, inhibition and induction effects of the herbal medicines on cytochrome P450s (CYPs) 1A2, 2C9, 2C19, 2D6 and 3A4 as well as P-glycoprotein (P-gp) were investigated. Methods Herbal medicines – Lessertia frutescens, Hypoxis hemerocallidea, Kalanchoe integra and Taraxacum officinale were sourced from Medico Herbs, South Africa were identified by experts from Compton Herbarium, South African National Biodiversity Institute, Cape Town. Moringa oleifera, Echinacea purpurea and Kalanchoe crenata were obtained from the repository of the National Centre for Natural Product Research (NCNPR), University of Mississippi, USA. Reversible inhibitory effect of aqueous and methanol herbal extracts were evaluated in recombinant CYPs applying the fluorescent metabolites at specified excitation/emission wavelengths; CYP1A2 (3-cyano-7-hydroxycoumarin (CHC); 405/460 nm), CYP2C9, CYP2C19 and CYP3A4 (7-hydroxy-4-(trifluoromethyl)-coumarin (HFC); 405/535 nm) and CYP2D6 (7-hydroxy-4-(aminomethyl)-coumarin (HAMC); 390/460 nm). Comparative studies in human liver microsomes (HLM) and recombinant CYPs were conducted to investigate the inhibitory effect of methanol herbal extracts and fractions on 6β testosterone hydroxylation activity. Time dependent inhibitory (TDI) effect of the herbal extracts were evaluated applying the IC50 shift fold, normalized ratio and the NADPH-, time- and concentration-dependent approaches. Influence of herbal extracts on metabolic clearance of testosterone was assessed in both HLM and human hepatocytes. The effects of each herbal extract on expression of CYP1A2, CYP3A4 and MDR1 genes were evaluated in activated human pregnane X receptor (PXR) co-transfected HepG2 cells. Finally, the inhibitory effect of herbal extracts on P-gp was assessed using the calcein-acetoxymethyl ester (calcein-AM) uptake and the digoxin radiolabelled substrates in MDCKII-MDRI cells. Results The aqueous extracts of Moringa oleifera, Kalanchoe integra, Kalanchoe crenata, Echinacea purpurea and Lessertia frutescens demonstrated high risk of in vivo inhibition on CYPs 3A4 and 1A2 with Cmax/Ki >1.0. Methanol extracts of these herbal medicines also indicated potential risk of reversible drug interaction. The methanol extracts of M. oleifera, K. crenata and L. frutescens showed strong TDI effect on CYP3A4 with IC50 shift fold >1.5 and normalised ratio <0.7. Moringa oleifera intermediately reduced intrinsic clearance of testosterone in human hepatocytes (2 ≤ AUC ratio ≤ 5) when scaled up to humans. Methanol extracts of Echinacea purpurea up-regulated the expression of CYP1A2, CYP3A4 and MDR1 genes in activated PXR. Kalanchoe crenata and Echinacea purpurea indicated strong inhibition on P-gp by reducing transport of digoxin across hMDR1-MDCKII cell monolayer from basolateral to apical with IC50 values of 18.24 ± 2.52 μg/mL and 24.47 ± 4.97 μg/mL, respectively. Conclusion The herbal medicines especially M. oleifera, K. integra and E. purpurea have the potential to cause herb-drug interaction in vivo if sufficient hepatic concentration is achieved in humans.
Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies
(Stellenbosch : Stellenbosch University, 2018-12) Kumar, Saneesh; Rosenkranz, Bernd; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology
Introduction Traditional, complementary and alternative medicines have been used to treat various health conditions. The use of such medicines among HIV/AIDS and TB patients in sub- Saharan Africa has increased considerably, and within this context, questions have been raised about the medical use of herbs or extracts as treatment alternatives without adequate clinical testing and without monitoring of adverse effects once on the market. Furthermore, potential herb-drug interactions (HDI) have been predicted based on the pharmacological and pharmacokinetic properties of prescription medications and the phytoconstituents within the herbs. This study investigated the potential of six popular African herbs consumed by HIV/AIDS and TB patients, viz., Withania somnifera, Glycyrrhiza glabra, Astragalus membranaceus, Inula helenium, Althaea officinalis and Ocimum basilicum, to inhibit the cytochrome P450 enzyme CYP2B6 and the esterase-mediated metabolism pathway of rifampicin and their ability to induce CYP3A4 and CYP2B6. The study was undertaken in four phases: (1) qualitative assessment of various classes of phytocompounds present in each herbal extract by biochemical phytoprofiling, (2) study of the potential inhibitory effects of the extracts on cytochrome CYP2B6 and on the metabolism pathway of rifampicin to 25-O-desacetyl rifampicin by in vitro assays using human liver microsomes (HLM), (3) analysis of the potential inducing effects of the herbal extracts on mRNA expression of CYP2B6 and CYP3A4 in HepG2 cell lines, using reverse transcription polymerase chain reaction (RT-PCR) and agarose gel electrophoresis (AGE), and (4) fingerprint analysis, identification and relative quantification of the major phytoconstituents present in each extract and prediction of compounds which may cause HDI by liquid chromatography-mass spectrometry coupled with photo diode array detection (LC-MS/PDA). Methods Dried roots of Withania somnifera, Glycyrrhiza glabra, Astragalus membranaceus, Inula helenium, Althaea officinalis and dried leaves and inflorescence of Ocimum basilicum were obtained from Pharma Germania, South Africa. Aqueous, methanol, ethanol and ethyl acetate extracts were prepared and analysed using biochemical tests to identify the presence of various classes of phytocompounds. HLM assays were conducted to evaluate the inhibitory potential of each extract on the CYP2B6-mediated metabolism of efavirenz to 8-Hydroxy efavirenz, and the biotransformation of rifampicin to 25-O-desacetyl rifampicin. The protocol included the incubation of the herbal extract, HLM, co-factors and substrates in phosphate buffer for 30 min at 37 oC, termination of reaction and HPLC analysis of the supernatant from the centrifuged assay sample (at 245 nm for efavirenz and its metabolite, and 254 nm for rifampicin and its metabolite). The half-maximal inhibitory concentrations (IC50) for the active extracts were calculated based on the percentage of remaining activity relative to the control. Time-dependent inhibition (TDI) IC50 fold-shift was evaluated using 30 min pre-incubation with NADPH, followed by incubation with substrate in buffer for another 30 min, using six concentrations (1-200 𝜇g/mL) of the herbal extract. CYP2B6 and CYP3A4 mRNA expression assays were conducted for measuring the induction potential of the extracts, where the 50% cytotoxic concentration (CTC50) of all herbal extracts was determined by screening them 1000.00- 31.25 𝜇g/mL) against HepG2 cells. The HepG2 cells were incubated for 24 h with the CTC50 concentration, for each herb. This was followed by extraction and purification of total mRNA and its expression through RT-PCR, followed by AGE. Relative sample expression levels were calculated and represented as fold-response levels of induction relative to a cell control (using rifampicin and dexamethasone as positive controls). LC-MS/PDA was used to identify and relatively quantify the potential phytochemical constituents in each extract. Results O.basilicum, G.glabra I.helenium and A.membranaceus contained most of the relevant groups of phytocompounds such as flavonoids, phenols, alkaloids, glycosides and terpenoids based on the biochemical qualitative analysis. The aqueous and methanolic extracts of O.basilicum showed reversible and time-dependent inhibition of CYP2B6 (TDI IC50s 33.35 𝜇g/mL, 4.93 𝜇g/mL, IC50 shift-fold >1.5 for both extracts), while the methanolic and ethanolic extracts inhibited the formation of 25-O-desacetyl rifampicin (IC50s 31 𝜇g/mL, 8.94 𝜇g/mL). The methanolic extract of O.basilicum showed the highest TDI with a 7.4-fold increase in the IC50. All extracts of I.helenium inhibited CYP2B6 (IC50s 63 𝜇g/mL, 89.43 𝜇g/mL) and rifampicin metabolism (IC50s 42.79 𝜇g/mL, 18.58 𝜇g/mL, 62.10 𝜇g/mL); the aqueous extract showed the highest TDI with a 3-fold increase in the IC50. Only the methanolic and ethyl acetate extracts of W.somnifera inhibited CYP2B6 (IC50 79.16 𝜇g/mL, 57.96 𝜇g/mL). TDI was mainly observed between the herbal extracts and CYP2B6. The ethanolic and methanolic extracts of A.officinalis induced CYP3A4, with 48%-foldresponse shift compared to the cell control (no inducer). The ethanolic extract of O.basilicum and G.glabra caused moderate induction of CYP3A4 and CYP2B6. The aqueous extract of A.membranaceus showed moderate and equal induction of CYP3A4 and CYP2B6 (36% fold-response increase). All extracts exhibited less than 2-fold induction (200%) response, in contrast to the positive controls, rifampicin and dexamethasone. Major phytocompounds detected in the LC-MS/PDA analysis of the extracts included flavonoids, phenols, glycosides, saponins and terpenoids. Relative amounts of the identified compounds were determined by comparison to standard calibrators, quercetin and gallic acid (expressed in mg/L equivalent units). Phenols such as rosmarinic acid (approximately 2298 mg/L in the aqueous extract) and caftaric acid were found in O.basilicum extracts along with the flavonoids salvigenin, rutin and isoquercetin and other compounds such as linalool, hydroxyjasmonic acid and eucommiol. The aqueous extract of I.helenium contained mostly polyphenols such as chlorogenic and caffeoylquinic acids, whereas other solvent extracts contained the sesquiterpenoid tanacetol A, helenin (isoalantolactone) and macrophyllilactone B. The methanolic and ethyl acetate extracts of W.somnifera comprised of withaperuvin, isopelletierine, salvigenin, withanolides and withaferin A (approximately 1117 mg/L in the ethyl acetate extract), and the extracts of A.membranaceus contained mainly calycosin, formononetin, astragalosides I and IV. The extracts of A.officinalis mainly comprised of quinic acid and altheahexacosanyl lactone derivatives (approximately 3874 mg/L in the methanol extract), d-galacturonic acid monohydrate, phloretin along with the fatty acid trihydroxy-octadecenoic acid, and the G.glabra extract mainly consisted of glabridin, liquiritin apioside, liquiritigenin and licochalcones. Conclusion A.membranaceus, I.helenium, O.basilicum and W.somnifera have been shown to contain astragalosides, alantolactones, phenolic acids and withanolides that may inhibit drug metabolising enzymes such as CYP2B6, CYP3A4 and the enzymes responsible for metabolism of rifampicin (including B-esterases). A.officinalis and G.glabra can cause moderate induction of CYP3A4 due to the higher concentration of lactones and chalcones present in their extracts. These in vitro findings may be relevant for clinical use of these herbs together with conventional medicines metabolised by these enzymes, if sufficient hepatic concentrations are attained in humans. The results of this study will help to guide planning and designing of clinical trials to confirm the potential relevance of HDI in patients.
Pharmacokinetics and dosing rationale of Para-Aminosalicylic acid in children and the evaluation of the in vitro metabolism of Ethionamide, Terizidone and Para-aminosalicylic acid
(Stellenbosch : Stellenbosch University, 2012-03) Liwa, Anthony Cuthbert; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology.
ENGLISH ABSTRACT: BACKGROUND: The emergence of mycobacterium tuberculosis resistance to first line drugs has renewed interest in second-line anti-tuberculosis drugs. Generally, Paraaminosalicylic acid (PAS) is less potent and frequently more toxic than the first line drugs. Furthermore, the pharmacokinetics of PAS in children has not been well characterized. AIMS: The aims of the present study were (1) to determine the pharmacokinetics of PAS in pediatric patients, (2) to describe the discrepancy between children and adult pharmacokinetics and the appropriate dosing regimen of PAS and (3) to investigate the potential of the second-line anti-tuberculosis drugs PAS, terizidone and ethionamide (often used as first-line drug in children) to inhibit the catalytic activities of CYP450 1A2 and 2C9. PATIENTS: Twenty two patients with drug resistant tuberculosis were included in the study. Ten patients were children with mean age of 4.2 years (range: 1 to 12 years). Twelve patients were adults with mean age of 31.3 years (range: 18 to 53). 4 children (40%) and 4 adults (33.3%) were HIV positive and were on ART. METHODS: Children received 75 mg/kg twice daily on the first visit and after two weeks they received 150 mg/kg once. Adults received a standard 4 g twice daily. Blood samples were taken at different time points after the dose. In the additional study, the inhibitory effects of PAS, ethionamide and terizidone on phenacetin O-deethylation, a marker substrate of CYP1A2 and diclofenac 4’-hydroxylation, a marker substrate of CYP2C9, were studied using human liver microsomes. RESULTS: For the 75 mg/kg dose, the mean AUC was 233.3 =g•h/ml and the mean CL was 10.4 l/h/kg. The mean of the observed Cmax of the drug was 45.4 =g/ml and the mean Tmax was 4.8 hrs. For the 150 mg/kg dose, the mean AUC of PAS was 277.9 =g•h/ml and the mean CL was 47.1 l/h/kg. The mean of the observed Cmax of the drug was 56.5 =g/ml and the mean Tmax was 4.8 hrs. On the first visit the mean AUC was 368 =g•h/ml and the mean CL was 13.2 l/h/kg. The mean of the observed Cmax of PAS was 51.3 =g/ml and the mean Tmax was 5.2 hrs. On the second visit the mean AUC was 230 =g•h/ml and the mean CL was 23.9 l/h/kg. The mean of the observed Cmax of PAS was 37.6 =g/ml and the mean Tmax was 5.2 hrs. The comparisons between pharmacokinetics profile of PAS and patients characteristics e.g. age, indicated no statistically significant differences between children (both treatment regimens) and adult patients as well as HIV positive and negative patients. In the in vitro study, all drugs demonstrated no inhibition potency towards the investigated CYP450 enzymes. CONCLUSIONS:The dose of 75 mg/kg twice daily in children appears to be appropriate to achieve serum concentration above the PAS minimum inhibitory concentration of approximately 1 =g/ml. PAS, ethionamide and terizidone are unlikely to affect the metabolism of concomitantly administered medications that are metabolized by either CYP450 1A2 and/or 2C9 isoenzymes.

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