**10. References**


Prediction of Partition Coefficients and Permeability of Drug Molecules in Biological

*Journal of Organic Chemistry* 75 (9), 3021-3026.

*of Pharmaceutical Sciences* 99 (3), 1500-1515.

Toronto, Ontario, M5C 1T4, Canada.

13188.

(14), 2158-2165.

(1-2), 82-90.

40 (5), 385-403.

Dekker, New York, 2000.

*Liquid Chromatography* 11 (7), 1441-1456.

*Chromatography* 15 (15-16), 2769-2785.

Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and… 125

Abraham, M. H. & Acree, W. E., Jr. (2010b) Solute descriptors for phenoxide anions and

Abraham, M. H. & Acree, W. E., Jr. (2010c) The transfer of neutral molecules, ions and ionic

Abraham, M. H. & Acree, W. E., Jr. (2010d) The transfer of neutral molecules, ions and ionic

Abraham, M. H.; Smith, R. E.; Luchtefeld, R.; Boorem, A. J.; Luo, R. & Acree, W. E., Jr. (2010)

Abraham, M. H. (2011) The permeation of neutral molecules, ions and ionic species: brain permeation as an example. *Journal of Pharmaceutical Sciences*, 100, (5), 1690-1701. Acree, W. E., Jr. & Abraham, M. H. (2002) Solubility of crystalline nonelectrolyte solutes in

Ahmed, H.; Poole, C. F. & Kozerski, G. E. (2007) Determination of descriptors for organo-

Ahmed, H. & Poole, C. F. (2006a) Distribution of neutral organic compounds between n-

Ahmed, Hamid & Poole, Colin F. (2006b) Model for the distribution of neutral organic

Alam, M. I.; Beg, S.; Samad, A.; Baboota, S.; Hohli, K.; Ali, J.; Ahuja, A. & Akbar, M. (2010)

Amidon, G. L.; Lennenas, H.; Shah, V. P. & Crison, J. R. (1995) A theoretical basis for a

Begley, D. J.; Khan, E. U.; Rollinson, C. & Abbott, J. (2000) in 'The blood-brain barrier and

Berthod, A.; Han, Y. Il. & Armstrong, D. W. (1988) Centrifugal partition chromatography. V.

Berthod, A.; Menges, R. A. & Armstrong, D. W. (1992) Direct octanol-water partition

general solvation model. *Journal of Solution Chemistry* 31 (4), 293-303 ADME Boxes, version\*, Advanced Chemistry Development, 110 Yonge Street, 14th Floor,

partitioning. *Journal of Chromatography, A* 1169 (1-2), 179-192.

partition. *Journal of Chromatography, A* 1216 (45), 7882-7888.

pyridinium cations. *New Journal of Chemistry* 34 (10), 2298-2305.

their use to establish correlations of rates of reaction of anions with iodomethane.

species from water to ethylene glycol and to propylene carbonate; descriptors for

species from water to wet octanol. *Physical Chemistry Chemical Physics* 12 (40), 13182-

Prediction of solubility of drugs and other compounds in organic solvents. *Journal* 

organic solvents: mathematical correlation of benzil solubilities with the Abraham

silicon compounds by gas chromatography and non-aqueous liquid-liquid

heptane and methanol or N,N-dimethylformamide. *Journal of Separation Science* 29

compounds between n-hexane and acetonitrile. *Journal of Chromatography, A* 1104

Strategy for effective brain drug delivery. *European Journal of Pharmaceutical Science*

biopharmaceutic drug classification: the correlation in vitro drug product dissolution and in vivo bioavailability. *Pharmaceutical Research* 12 (3), 413-420. Arey, J. S.; Green, W. H., Jr. & Gschwend, P. M. (2005) The electrostatic origin of Abraham's solute polarity parameter. *Journal of Physical Chemistry B* 109 (15), 7564-7573. Atapattu, S. N. & Poole, C. F. (2009) Determination of descriptors for semivolatile

organosilicon compounds by gas chromatography and non-aqueous liquid-liquid

drug delivery to the CNS, Ed by Befley, D.J.; Bradbury, M. W. & Kreuter, J., Marcel

Octanol-water partition coefficients, direct and indirect determination. *Journal of* 

coefficient determination using co-current chromatography. *Journal of Liquid* 

in humans: a quantitative structure-activity relationship analysis. *Toxicological Sciences* 76 (2), 384-391.


Abraham, M. H. (2004) The factors that influence permeation across the blood-brain barrier.

Abraham, M. H.; Ibrahim, A. & Zissimos, A. M. (2004) Determination of sets of solute

Abraham, M. H. & Martins, F. (2004) Human skin permeation and partition: General linear

Abraham, M. H.; Ibrahim, A. & Acree, W. E. Jr., (2005) Air-to-blood distribution of volatile

Abraham, M. H. & Ibrahim, A. (2006) Air to fat and blood to fat distribution of volatile

Abraham, M. H.; Ibrahim, A. & Acree, W. E (2006a) Air to brain, blood to brain and plasma

Abraham, M. H.; Ibrahim, A.; Zhao, Y. & Acree, W. E., Jr. (2006b) A data base for partition

Abraham, M. H. & Ibrahim, A. (2007) Blood or plasma to skin distribution of drugs: a linear free energy analysis. *International Journal of Pharmaceutics* 329 (1-2) 129-134. Abraham, M. H.; Ibrahim, A. & Acree, W. E., Jr. (2007a) Air to liver partition coefficients for

Abraham, M. H.; Sanchez-Moreno, R.; Cometto-Muniz, J. E. & Cain, W. S. (2007b) A

Abraham, M. H.; Acree, W. E., Jr.; Mintz, C. & Payne, S. (2008b) Effect of anesthetic structure

Abraham, M. H.; Acree, W. E., Jr. & Cometto-Muniz, J. E. (2009a) Partition of compounds from water and from air into amides. *New Journal of Chemistry* 33 (10), 2034-2043. Abraham, M. H.; Gil-Lostes, J. & Fatemi, M. (2009b) Prediction of milk/plasma

Abraham, M. H. & Acree, W. E., Jr. (2010a) Equations for the transfer of neutral molecules

*European Journal of Medicinal Chemistry* 39 (3), 235-240.

*European Journal of Medicinal Chemistry* 41 (4), 494-502.

analyses. *Chemical Research in Toxicology* 19 (6), 801-808.

*Medicinal Chemistry* 41 (12), 1430-1438.

*Sciences* 76 (2), 384-391.

(1-2), 29-47.

(5), 904-911.

751.

485.

1006-1015.

*Sciences* 97 (6), 2373-2384.

*Medicinal Chemistry* 44 (6), 2452-2458.

in humans: a quantitative structure-activity relationship analysis. *Toxicological* 

descriptors from chromatographic measurements. *Journal of Chromatography, A* 1037

free-energy relationship analyses. *Journal of Pharmaceutical Sciences* 93 (6), 1508-1523.

organic compounds: a linear free energy analysis. *Chemical Research in Toxicology* 18

organic compounds and drugs: Linear free energy analyses. *European Journal of* 

to brain distribution of volatile organic compounds: linear free energy analyses.

of volatile organic compounds and drugs from blood/plasma/serum to brain, and an LFER analysis of the data. *Journal of Pharmaceutical Sciences* 95 (10), 2091-2100. Abraham, M. H.; Ibrahim, A. & Acree, W. E., Jr. (2006c) Air to muscle and blood/plasma to

muscle distribution of volatile organic compounds and drugs: linear free energy

volatile organic compounds and blood to liver partition coefficients for volatile organic compounds and drugs. *European Journal of Medicinal Chemistry* 42 (6), 743-

quantitative structure-activity analysis on the relative sensitivity of the olfactory and the nasal trigeminal chemosensory systems. *Chemical Senses* 32 (7), 711-719. Abraham, M. H.; Ibrahim, A. & Acree, W. E, Jr. (2008a) Air to lung partition coefficients for

volatile organic compounds and blood to lung partition coefficients for volatile organic compounds and drug. *European Journal of Medicinal Chemistry* 43 (3), 478-

on inhalation anesthesia: implications for the mechanism. *Journal of Pharmaceutical* 

concentration ratios of drugs and environmental pollutants. *European Journal of* 

and ionic species from water to organic phases. *Journal of Organic Chemistry* 75 (4),


Prediction of Partition Coefficients and Permeability of Drug Molecules in Biological

*of Chemical Information and Modeling* 48 (7), 1289–1303.

using reverse-phase HPLC *Chemosphere* 10 (1), 73-83.

*International Journal of Pharmaceutics* 395, 182-197.

*Pharmaceutical Research* 18 (7) 992-998.

*Journal of Medicinal Chemistry* 49 (6), 3948-3954.

153-163.

(5), 499-513.

26.

*Reviews* 56 (9), 1273-1289.

Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and… 127

Lipinski, C. A.; Lombardo, F.; Dominy, B. W. & Feeney, P. J. (2001) Experimental and

Llinàs, A.; Glen, R. C. & Goodman, J. M. (2008) Solubility challenge: can you predict

Lukyanov, A. N. & Torchilin, V. P. (2004) Micelles from lipid derivatives of water-soluble

McDuffie, B. (1981) Estimation of octanol/water partition coefficients for organic pollutants

Menges, R. A.; Bertrand, G. L. & Armstrong, D. W. (1990) Direct measurement of

Michaels A. S, Chandrasekaran S. K, & Shaw J. E. (1975).Drug permeation through human skin: theory and *in vitro* experimental measurement. *AIChE Journal* 21 (5), 985–996. Mintz, C.; Clark, M.; Acree, W. E., Jr. & Abraham, M. H. (2007) Enthalpy of solvation

Abraham model. *Journal of Chemical Information and Modeling* 47 (1), 115-121. Monteiro-Riviere, N. A.; Inman, A. O.; Mak, V.; Wertz, P. & Riviere, J. E. (2001) Effect of

Mutelet, F. & Rogalski, M. (2001) Experimental determination and prediction of the gas-

Netzlaff, F.; Schaefer, U. F.; Lehr, C.-M.; Meiers, P.; Stahl, J.; Kietzmann, M. & Niedorf, F.

Nicholls, A.; Mobley, D. L.; Guthrie, J. P.; Chodera, J. D.; Bayly, C. I.; Cooper, M. D. & Pande,

Platts, J. A.; Butina, D.; Abraham, M. H. & Hersey, A. (1999) Estimation of molecular linear

Poole, S. K. & Poole, C. F. (2003) Separation methods for estimating octanol-water partition

Qian, J. & Poole, C. F. (2007) Distribution of neutral organic compounds between n-heptane and fluorine-containing alcohols. *Journal of Chromatography, A* 1143 (1-2), 276-283.

*Chemical Information and Computational Science* 39 (5), 835-845.

coefficients. *Journal of Chromatographty B* 797 (1-2), 3-19.

for computational chemistry. *Journal of Medical Chemistry* 51 (4) 769-779. Ottaviani, G.; Martel, S. & Carrupt, P.-A. (2006) Parallel artificial membrane permeability

computational approaches to estimate solubility and permeability in drug discovery and development settings. *Advances in Drug Delivery Reviews* 46 (1-3), 3-

solubilities of 32 molecules using a database of 100 reliable measurements. *Journal* 

polymers as delivery systems for poorly soluble drugs. *Advanced Drug Delivery* 

octanolwater partition coefficients using centrifugal partition chromatography with a back-flushing technique. *Journal of Liquid Chromatography* 13 (15), 3061-3077. Mensch, J.; Jaroskova, L.; Anderson, W.; Mells, A.; Mackle, C.; Verreck, G.; Brewster, M. E. &

Augustinjns, P. (2010) Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

correlations for gaseous solutes dissolved in water and in 1-octanol based on the

selective lipid extraction from different body regions on epidermal barrier function.

liquid n-hexadecane partition coefficients. *Journal of Chromatography A* 923 (102),

(2006) Comparison of bovine udder skin with human and porcine skin in percutaneous permeation experiments. *ATLA, Alternatives to Laboratory Animals* 34

V. S. (2008) Predicting small-molecule solvation free energies: an informal blind test

assay: A new membrane for the fast prediction of passive human skin permeability.

free energy relation descriptors using a group contribution approach. *Journal of* 


Charlton, A. K.; Daniels, C. R.; Acree, W. E., Jr. & Abraham, M. H. (2003) Solubility of

Cruciani, G.; Pastor, M. & Guba, W. (2000) VolSurf: a new tool for the pharmacokinetic

Eixarch, H.; Haltner-Ukomadu, E.; Beisswenger, C. & Bock, U. (2010) Drug delivery to the

Faller, B.; Grimm, H. P.; Loeuillet-Ritzler, F.; Arnold, S. & Briand, X. (2005) High-throughput

Friend, D. R. (1992) *In vitro* skin permeation techniques. *Journal of Controlled Re*lease 18, 235-

Gao, X.; Yu, C. H.; Tam, K. Y. & Tsang, S. C. (2005) New magnetic nano-absorbent for the

Guthrie J. P. (2009) A blind challenge for computational solvation free energies: introduction

Hathout, R. M.; Woodman, T. J.; Mansour, S.; Mortada, N. D.; Geneidi, A. S. & Guy, R. H.

Henchoz, Y.; Romand, S.; Schuppler, J.; Rudaz, S.; Veathey, J.-L. & Carrupt, P. A. (2010)

Hewitt, M.; Cronin, M. T. D.; Enoch, S. J.; Madden, J. C.; Roberts, D. W. & Dearden, J. C.

Holbrook K A. & Odland G F. (1974) Regional differences in the thickness (cell layers) of the

Howard, P. H. & Meylan, W. M. (1997) Handbook of Physical properties of Organic

Ishihama, Y. & Asakawa, N. (1999) Characterization of the lipophilicity scales using vectors

Karunasekara, T. & Poole, C. F. (2010) Model for the partition of neutral compounds between n-heptane and formamide. *Journal of Separation Science* 33 (8), 1167-1173. Keck, C.; Kobierski, S.; Mauludin, R. & Muller, R. H. (2008) Second generation of drug

Li, H.; Yap, C. W.; Ung, C. Y.; Xue, Y.; Cao, Z. W. & Chen, Y. Z. (2005) Effect of selection of

Li, Q.-S.; Li, Z. & Wang, S. (2008) Solubility of trimethoprim (TMP) in different organic

and overview. *Journal of Physical Chemistry B* 113 (14) 4501-4507.

*European Journal of Pharmaceutical Sciences* 40 (3), 188-196.

*Chemical Information and Modeling* 49 (11), 2572–2587.

*Solution Chemistry* 32 (12), 1087-1102.

*Biology and Pharmacology* 3, 1-14.

*Medicinal Chemistry* 48 (7), 2571-2576.

*Biomedical Analysis* 38 (2), 197-203.

detections. *Electrophoresis*, 31 (5), 952-964.

Chemicals, CRC Press, Boca Raton, 1997.

*Information and Modeling* 45 (5) 1376-1384.

*Dermatology* 62 (4), 415-422.

(Suppl. 2), S29-S39.

248.

1312.

(24), 124-128 .

crystalline nonelectrolyte solutes in organic solvents: mathematical correlation of acetylsalicylic acid solubilities with the Abraham general solvation model. *Journal of* 

optimization of lead compounds. *European Journal of Pharmaceutical Sciences* 11

lung: permeability and physicochemical characteristics of drugs as the basis for a pulmonary Biopharmaceutical Classification System (pBCS). *Journal of Epithelial* 

lipophilicity measurement with immobilized artificial membranes. *Journal of* 

determination of n-octanol/water partition coefficients. *Journal of Pharmaceutical and* 

(2010) Microemulsion formulations for the transdermal delivery of testosterone.

High-throughput log P determination by MEEKC coupled with UV and MS

(2009) In silico prediction of aqueous solubility: the solubility challenge. *Journal of* 

human stratum corneum: an ultrastructural analysis. *The Journal of Investigative* 

from solvation energy descriptors. *Journal of Pharmaceutical Sciences* 88 (12), 1305-

nanocrystals for delivery of poorly soluble drugs: smartcrystal technology. *Dosis*, 2

molecular descriptors on the prediction of blood-brain barrier penetrating and nonpenetrating agents by statistical learning methods. *Journal of Chemical* 

solvents from (278 to 333) K. *Journal of Chemical and Engineering Data* 53 (1), 286-287.


**6** 

**Variability of Plasma Methadone** 

*Universiti Sains Malaysia, Kubang Kerian, Kelantan,* 

*Institute for Research in Molecular Medicine (INFORMM),* 

*Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan,* 

<sup>3</sup>*Pharmacogenetic Research Group,* 

*Malaysia* 

**Concentration in Opiate Dependent** 

**Receiving Methadone: A Personalised** 

Nasir Mohamad1,3, Nor Hidayah Abu Bakar2, Tan Soo Choon3, Sim Hann Liang3, NIM Nazar3, Ilya Irinaz Idrus3 and Rusli Ismail3 *1Department of Emergency Medicine, School of Medical Sciences, Health Campus,* 

*2Department of Pathology, Hospital Raja Perempuan Zainab II, Kota Bharu, Kelantan,* 

**1.1 Methadone and methadone maintenance therapy (MMT): An overview** 

Methadone acts on the opioid receptors and produces many of the same effects of morphine and heroin. In the treatment of opioid dependence, methadone has cross-tolerance with other opioid, including heroin and morphine and a long duration of effect. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these

Methadone is a misunderstood drug and ignorance about it is common. Even professionals, physicians and pharmacists who are supposed to be the "guardians" of MMT receive very little training about the very medication that they are responsible for. To compound the issue, addiction is mostly viewed not as a disease and its care is frequently relegated to the lay public, at least until very recently. In Malaysia, addiction has solely been under the charge of "*Agensi Anti Dadah Kebangsaan"* (AADK), an agency that has mainly adopted a criminal approach to addiction. However, this has recently changed in Malaysia. Addiction is now recognized as a medical illness, under the purview of the medical professionals. Nevertheless, many in the medical profession only have a rudimentary understanding of addiction. Most physicians, pharmacists and nurses receive very little training about addiction and much less regarding methadone. Thus, generally, both medical and other caregivers have very limited knowledge about addiction and much less about methadone. They have generally been taught to approach addiction as a character disorder and

**1. Introduction** 

substances.

administer methadone as a substitute.

**Approach Towards Optimizing Dose** 

