EDCTP Alumni Network

Fostering excellence and collaboration in the next generation of researchers

All Profiles

Professor Collen Masimirembwa

Call Senior Fellowship (SF)
Programme EDCTP2
Start Date 2018-04-01
End Date 2023-03-31
Project Code TMA2016SF1508
Status Active

Title

Pharmacogenomics Research And Clinical Excellence in the Treatment of Infectious Diseases in African

Host Organisation

Institution Country
African Institute of Biomedical Science & Technology (AIBST) Zimbabwe

Sites

Wilkins Infectious Disease Hospital (Harare)

Phd Study

Title University Start Date End Date
Medical Biochemistry and Biophysics Karolinska Institute, Sweden 1995-01-02 1995-11-30

Students Supervised

Type Name Title University Start Date End Date
Phd Nyarai Shoko Ms UCT 2014 2017
PhD Benjamin Ebeshi Dr AOU 2011 2011
MPhil Lovejoy Nleya Mr UZ 2012 2016
PhD Britta Kjellander Dr Gothenburg Univ 2010 2010
MPhil Winnie Muzorandi Mrs UZ 2011 2015
PhD Nicholas Mwaura Mr UCT 2011 2014

Publications

262
187
205
154
119
171
129
126
128
129
Call Senior Fellowship (SF)
Programme EDCTP1
Start Date 2012-11-01
End Date 2014-12-31
Project Code TA.2011.40200.052
Status Completed

Title

A prospective study to evaluate a pharmacogenetic-guided dosing algorithm based on patient CYP2B6 genotype compared to the empirical standard dose in the safe and efficacious use of efavirenz in HIV/AIDS patients in Zimbabwe

Objectives

Primary Objectives: 1. To compare efavirenz exposure levels in patients in whom the initiation dose is based on a pharmacogenetic algorithm with those in patients given the standard dose 2. To compare HIV viral load suppression and CD4 counts in patients in whom efavirenz dose is based on a pharmacogenetic algorithm with those in patients given the standard dose 3. To compare the incidences and severity of efavirenz associated adverse drug reactions; liver function, skin hypersensitivity reactions and central nervous system (CNS) effects in patients in whom the efavirenz dose is based on a pharmacogenetic algorithm with those given the standard dose 4. To validate the CYP2D6 genotyping method for use in the clinical study

Host Organisation

Institution Country
African Institute of Biomedical Science and Technology (AiBST) Zimbabwe

Study Design

Prospective randomised controlled trial

Sites

Wilkins Infectious Disease Hospital (Harare)
Chitugwiza Hospital, Opportunistic Infections Unit (Chitugwiza)

Results & Outcomes

HIV/AIDS and TB cohort in Zimbabwe. We have conclusively shown that the CYP2B6*6 genotype is predictive of high concentrations of Project Porftolio Page 333 of 622 efavirenz and predisposition to CNS sides effects and require only 200 mg of the drug instead of the standard 600 mg a day. We have also shown that for the other patients heterozygous, that those carrying one defect CYP2B6 allele and those without a defect should only be given 400 mg of efavirenz a day. Our findings are supported by a recent major study, ENCORE, which demonstrated the non-inferiority of 400 mg to the 600 mg efavirenz dose. This therefore represents the climax of our study which medicines control regulatory authorities should now consider towards revising the use of this drug. We have now engaged the Medicines Control Authority of Zimbabwe (MCAZ) and the National AIDS Council (NAC). We have also been on radio stations explaining our results to the public, an outreach that has been well received and patients phoned in expressing their appreciation of having the reason for their ADRs explained based on our study. The work has also resulted in secondary of achievements such as: (1) Establishment of a Clinical Trial Research Group whose purpose is to critically discuss the design and execution of clinical studies in African settings. (2) Four publications (3) Initiation of a Clinical Trial Unit (CTC) at one of the major hospitals in Zimbabwe, Chitungwiza General Hospital, for the conduct of Phase I Clinical Studies. (4) The completion of PhD studies and successful defence of the thesis in December 2014, by Milcah Dhoro on Pharmacogenetics of Efavirenz

Current Organisation

African Institute of Biomedical Science and Technology (AIBST)

Current Job Title

Chief Scientific Officer

Awards

2018 HUGO (Human Genome Organisation) International Africa Award for innovative research contribution in genomics in Africa – 5 000 USD.
2017 1st Prize Innovation Award, Gauteng Accelator Program (GAP) South Africa – 500 000 Rands.
2017 Research Council of Zimbabwe Robert Gabriel Mugabe Outstanding Research Award (Awarded by the President of Zimbabwe through RCZ) – 15 000 USD
2014 Certificate of Excellence in recognition of pioneering work in the field of Forensic DNA Services in Zimbabwe (Awarded by the Vice-President of Zimbabwe)
1996 Certificate of Distinction in Biochemistry, President Robert Mugabe, Government of Zimbabwe (Awarded by the President of Zimbabwe) – 10 000 USD.

Students Supervised

Type Name Title University Start Date End Date
MPhil Lovejoy Nleya Mr University of Zimbabwe 2012 2016
PhD Nyarai Shoko Miss University of Cape Town 2014 2014
Molecular Diagnostics Vanessa Chasi Miss National University of Science & Technology 2014 2015
Drug-Herb Interactions Winnie Muzorandi Miss University of Zimbabwe 2011 2015
PGx Milcah Dhoro Ms UZ 2011 2014
Molecualr Virology Benjamin Chimkangara Mr UZ 2012 2015
Medicinal Chem. Nicholas Mwaura Mr UCT 2011 2014
ADME/Med. Chem. Roslyn Thelingwani Miss UCT 2008 2012
PGx Margaret Oluka Miss UoN 2006 2012
ADME/Med. Chem. Britta Kjellander Miss Gothenburg Univ 2010 2010
PGx Benjamin Ebeshi Mr OAU 2011 2011
PGx Alice Matimba Miss UCT 2009 2009
HIV Drug Resistance Justen Manasa Mr UZ 2008 2008
PGx Christopher Nyakutira Mr UZ 2008 2008
Drug-Herb Interactions Luther Gwaza Mr UZ 2008 2008
PK Simbarashe Zvada Mr UZ 2011 2011
PGx Emmanuel Chigutsa Mr UZ 2010 2010
ADMET Roslyn Thelingwani Miss UZ 2007 2007
ADMET Roslyn Thelingwani Miss UZ 2005 2005
ADMET AnnCharlotte Egnell Ms Gothenburg Univ. 2002 2002
ADMET Lovisa Afzelius Ms Gothenburg Univ. 1999 1999
ADMET Anna Åhgren Ms Gothenburg Univ. 2001 2001
ADMET/PK Tashinga Bapiro Mr UZ 2004
ADMET/Med Chem. Lovisa Afzelius Miss Uppsala Univ 2004 2004
ADMET Rose Hayeshi Miss UZ 2008 2008

Memberships

Role Committee/board Start Date End Date
Member and Secretary IUPHAR (International Union of Pharmacology) Drug Metabolism and Transporters Section 2014
Member IUPHAR (International Union of Pharmacology) Pharmacogenetics Section 2014
International Advisor Malaysian Society for the Advancement of Pharmacogenomics (MSAP 2005 2010
President The African Society of Drug Metabolism and Development 2009
Member Laboratory Committee of the Medicines Control Authority of Zimbabwe (MCAZ) 2004 2014
Fellow and Dean of the College of Life Sciences Zimbabwe Academy of Science (ZAS) 2007 2016
Chairperson & Founding Member African Pharmacogenomics Consortium 2003
AAS Governing Council Southern African Representative The African Academy of Sciences Governing Council 2017
President African Pharmacogenomics Consortium 2018

Education

Institution Degree Year
Uinversity of Zimbabwe, Zimbabwe BSc (Hons) (Biochemistry), University of Zimbabwe 1989-05-04
University of Zimbabwe, Zimbabwe DPhil (Biochemistry), 1994-02-04
Karolinska Institute, Sweden PhD (Medical Biochemistry and Biophysics 1995-02-05
,

Areas Of Specialisation

Human Immuno-deficiency Virus (HIV)

Grants

Commercial development of a pharmacogenetic test for the safe use of the anti-retroviral drug efavirenz
Grant Code:
Source of funding:
Gauteng Accelerator Program (GAP)
Amount:
35332.32
Role:
Principal Investigator
Start Date:
2017-01-01
End Date:
2018-01-01
Capacity Development Research & Regulatory meetings/courses
Grant Code:
Source of funding:
Norvatis
Amount:
110000.00
Role:
Principal Investigator
Start Date:
2012-01-01
End Date:
2014-01-01
WHO-TDR DMPK Centre in Africa
Grant Code:
Source of funding:
WHO-TDR
Amount:
60000.00
Role:
Principal Investigator
Start Date:
2010-01-01
End Date:
2012-01-01
Pharmacogenetics of efavirenz
Grant Code:
Source of funding:
TWAS
Amount:
10000.00
Role:
Principal Investigator
Start Date:
2008-01-01
End Date:
2009-01-01
1st ADME workshop in South Africa
Grant Code:
Source of funding:
IUPHAR
Amount:
5000.00
Role:
Principal Investigator
Start Date:
2002-01-01
End Date:
2002-01-01
Praziquantel metabolism and pharmacokinetics
Grant Code:
Source of funding:
Merck Master Service Agreement.
Amount:
130000.00
Role:
Principal Investigator
Start Date:
2013-01-01
End Date:
2015-01-01
Research and Educational Activities
Grant Code:
Source of funding:
AstraZeneca
Amount:
239131.25
Role:
Principal Investigator
Start Date:
2003-01-01
End Date:
2007-01-01
Phase I Clinical Trial Unit
Grant Code:
Source of funding:
Norvatis
Amount:
150000.00
Role:
Principal Investigator
Start Date:
2016-01-01
End Date:
2016-01-01
DMPK & BAC education and research
Grant Code:
Source of funding:
ISP
Amount:
129216.60
Role:
Principal Investigator
Start Date:
2012-01-01
End Date:
2017-01-01
A prospective study to evaluate a pharmacogenetic-guided dosing algorithm based on patient CYP2B6 genotype compared to the empirical standard dose in the safe and efficacious use of efavirenz in HIV/AIDS patients in Zimbabwe
Grant Code:
TA.2011.40200.052
Source of funding:
European and Developing Countries Clinical Trials Partnership (EDCTP)
Amount:
Role:
Principal Investigator
Start Date:
2012-11-01
End Date:
2014-12-31
PK & PGx research and postgraduate training
Grant Code:
Source of funding:
ISP
Amount:
180000.00
Role:
Principal Investigator
Start Date:
2018-01-01
End Date:
2020-01-01
Commercial development of a pharmacogenetic test for the safe use of the anti-retroviral drug efavirenz
Grant Code:
Source of funding:
SANBIO BIOFISAII
Amount:
9893.05
Role:
Start Date:
2016-01-01
End Date:
2018-01-01
Strengthening of DMPK platform
Grant Code:
Source of funding:
European Union (EU)-AntiMal.
Amount:
360000.00
Role:
Principal Investigator
Start Date:
2008-01-01
End Date:
2011-01-01
DMPK & BAC education and research
Grant Code:
Source of funding:
ISP
Amount:
114859.20
Role:
Principal Investigator
Start Date:
2012-01-01
End Date:
2014-01-01
In vivo Biomarker of CYP3A activity
Grant Code:
Source of funding:
AstraZeneca
Amount:
216000.00
Role:
Principal Investigator
Start Date:
2017-01-01
End Date:
2018-01-01
Next Generation Biomedical Scientists
Grant Code:
Source of funding:
Wellcome Trust
Amount:
38500.00
Role:
Start Date:
2016-01-01
End Date:
2016-01-01
DMPK Research.
Grant Code:
Source of funding:
ISP
Amount:
19130.50
Role:
Principal Investigator
Start Date:
2008-01-01
End Date:
2008-01-01
Clinical Pharmacology of antibiotic drug resistance
Grant Code:
Source of funding:
BrfArM
Amount:
350000.00
Role:
Start Date:
2017-01-01
End Date:
2020-01-01
1st ADME workshop in South Africa
Grant Code:
Source of funding:
SANBIO BIOFISAII
Amount:
5000.00
Role:
Principal Investigator
Start Date:
2002-01-01
End Date:
2002-01-01
H3ABioNet
Grant Code:
Source of funding:
NIH
Amount:
300000.00
Role:
Co Principal Investgator
Start Date:
2018-01-01
End Date:
2022-01-01
DMPK Research and Training of Postgraduates
Grant Code:
Source of funding:
ISP
Amount:
92652.50
Role:
Principal Investigator
Start Date:
2009-01-01
End Date:
2011-01-01
Non-cold chain requiring molecular diagnostics in the treatment of a rural HIV/AIDS cohort
Grant Code:
Source of funding:
Saving African Families Enterprises
Amount:
50000.00
Role:
Principal Investigator
Start Date:
2014-01-01
End Date:
2015-01-01
1st ADME workshop in South Africa
Grant Code:
Source of funding:
AstraZeneca
Amount:
10000.00
Role:
Principal Investigator
Start Date:
2002-01-01
End Date:
2002-01-01
WHO-TDR DMPK Centre in Africa.
Grant Code:
Source of funding:
WHO-TDR
Amount:
70000.00
Role:
Principal Investigator
Start Date:
2008-01-01
End Date:
2009-01-01
Agreement for the Performance of ADME work for WHO-TDR
Grant Code:
Source of funding:
WHO-TDR
Amount:
36000.00
Role:
Principal Investigator
Start Date:
2007-01-01
End Date:
2007-01-01
Optimisation of AIDS-TB co-infection treatment research
Grant Code:
Source of funding:
European Union. EDCTP
Amount:
64000.00
Role:
Principal Investigator
Start Date:
2007-01-01
End Date:
2011-01-01
Pharmacogenomics Research And Clinical Excellence (PRACE)
Grant Code:
Source of funding:
European and Developing Countries Clinical Trials Partnership (EDCTP)
Amount:
500000.00
Role:
Principal Investigator
Start Date:
2018-01-01
End Date:
2022-01-01

Publications

Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modelling, and three-dimensional quantitative structure-activity relationship analysis
Authors:
L Afzelius, I Zamora, M Ridderström, TB Andersson, A Karlén, CM Masimirembwa , 129
Date:
2009-05-05
Journal:
Molecular pharmacology 59 (4)
Content:
CYP2B6 genotype is a strong predictor of systemic exposure to efavirenz in HIV-infected Zimbabweans.
Authors:
Maimbo M, Kiyotani K, Mushiroda T, Masimirembwa C, Nakamura Y.
Date:
2012-03-06
Journal:
Eur J Clin Pharmacol. 2012 Mar;68(3):267-71.
Content:
In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery.
Authors:
CM Masimirembwa, R Thompson, TB Andersson , 154
Date:
2001-05-05
Journal:
Combinatorial chemistry & high throughput screening 4 (3)
Content:
Lysosomal trapping of amodiaquine: impact on transport across intestinal epithelia models.
Authors:
Hayeshi R, Masimirembwa C, Mukanganyama S, Ungell AL
Date:
2008-09-29
Journal:
Biopharm Drug Dispos. 2008 Sep;29(6):324-34.
Content:
Exploration of enzyme-ligand interactions in CYP2D6 & 3A4 homology models and crystal structures using a novel computational approach.
Authors:
Kjellander B, Masimirembwa CM, Zamora I.
Date:
2007-05-31
Journal:
J Chem Inf Model. 2007 May-Jun;47(3):1234-47
Content:
Simulation of metabolism-based herb-drug interaction: towards safe and efficacious use of NIPRD-AM1.
Authors:
Adzu B, Mustapha KB, Masimirembwa C, Obodozie O, Kirim RA, Gamaniel KS. Avicenna J Phytomed
Date:
2013-03-03
Journal:
2013 Summer;3(3):201-
Content:
Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data
Authors:
XQ Li, A Björkman, TB Andersson, LL Gustafsson, CM Masimirembwa , 205
Date:
1996-05-05
Journal:
European journal of clinical pharmacology 59 (5-6
Content:
H3Africa and the African life sciences ecosystem: building sustainable innovation
Authors:
Dandara C, Huzair F, Borda-Rodriguez A, Chirikure S, Okpechi I, Warnich L, Masimirembwa C
Date:
2014-12-18
Journal:
OMICS. 2014 Dec;18(12):733-9
Content:
Building Capability for Clinical Pharmacology Research in Sub-Saharan Africa.
Authors:
Gutierrez MM, Pillai G, Felix S, Romero F, Onyango KO, Owusu-Agyei S, Asante KP, Barnes KI, Sinxadi P, Allen E, Abdulla S, Masimirembwa C, Munyoro M, Yimer G, Gebre-Mariam T, Spector J, Ogutu B
Date:
2017-04-05
Journal:
Clin Pharmacol Ther; 10.1002/cpt.695. [Epub ahead of print]
Content:
Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s
Authors:
TE Bapiro, AC Egnell, JA Hasler, CM Masimirembwa , 126
Date:
2001-05-05
Journal:
Drug Metabolism and disposition 29 (1),
Content:
Drug resistance mutations from whole blood proviral DNA among patients on antiretroviral drugs in Zimbabwe.
Authors:
Chimukangara B, Gwanzura L, Mitchell R, Katzenstein D, Masimirembwa C
Date:
2014-12-05
Journal:
Curr HIV Res. 2014;12(5):309-16
Content:
In vitro and in silico identification and characterization of thiabendazole as a mechanism-based inhibitor of CYP1A2 and simulation of possible pharmacokinetic drug-drug interactions.
Authors:
Thelingwani RS, Zvada SP, Dolgos H, Ungell AL, Masimirembwa CM
Date:
2009-06-03
Journal:
Drug Metab Dispos. 2009 Jun;37(6):1286-94
Content:
Practical Approach to Biobanking in Zimbabwe: Establishment of an Inclusive Stakeholder Framework.
Authors:
Matimba A, Tybring G, Chitereka J, Zinyama-Gutsire R, Dandara C, Bürén E, Dhoro M, Masimirembwa C
Date:
2016-04-15
Journal:
Biopreserv Biobank. 2016 Apr 15. [Epub ahead of print] PMID: 27082894
Content:
The effect of the Pheroid delivery system on the in vitro metabolism and in vivo pharmacokinetics of artemisone.
Authors:
Grobler L, Grobler A, Haynes R, Masimirembwa C. Thelingwani R, Steenkamp P, Steyn HS
Date:
2014-03-24
Journal:
Expert Opin Drug Metab Toxicol. 2014 Mar;10(3):313-25
Content:
Effect of NIPRISAN® on CYP3A4 activity in vitro.
Authors:
Adzu B, Masimirembwa C, Mustapha KB, Thelingwani R, Kirim RA, Gamaniel KS
Date:
2015-03-04
Journal:
Eur J Drug Metab Pharmacokinet. 2015 Mar;40(1):115-8.
Content:
Exploration of catalytic properties of CYP2D6 and CYP3A4 through metabolic studies of levorphanol and levallorphan.
Authors:
Bonn B, Masimirembwa CM, Castagnoli N Jr
Date:
2010-01-04
Journal:
Drug Metab Dispos. 2010 Jan;38(1):187-99.
Content:
Heterologous expression and kinetic characterization of human cytochromes P-450: validation of a pharmaceutical tool for drug metabolism research
Authors:
CM Masimirembwa, C Otter, M Berg, M Jönsson, B Leidvik, E Jonsson, ... , 129
Date:
1999-05-05
Journal:
Drug Metabolism and Disposition 27 (10),
Content:
Evaluation of the Partec flow cytometer against the BD FACSCalibur system for monitoring immune responses of human immunodeficiency virus-infected patients in Zimbabwe.
Authors:
Manasa J, Musabaike H, Masimirembwa C, Burke E, Luthy R, Mudzori J
Date:
2007-03-14
Journal:
Clin Vaccine Immunol. 2007 Mar;14(3):293-8.
Content:
Community burden of undiagnosed HIV infection among adolescents in Zimbabwe following primary healthcare-based provider-initiated HIV testing and counselling: A cross-sectional survey.
Authors:
Simms V, Dauya E, Dakshina S, Bandason T, McHugh G, Munyati S, Chonzi P, Kranzer K, Ncube G, Masimirembwa C, Thelingwani R, Apollo T, Hayes R, Weiss HA, Ferrand RA. PLoS Med
Date:
2018-07-25
Journal:
e1002360. doi: 10.1371/journal.pmed.1002360. eCollection
Content:
Kinetics and mechanistic investigation into the possible activation of imidazolium trans-[tetrachloridodimethyl-sulfoxideimidazoleruthenate(III)], NAMI-A, by 2-mercaptoethane sulfonate.
Authors:
Adigun RA, Martincigh B, Nyamori VO, Omondi B, Masimirembwa C, Simoyi RH.
Date:
2014-09-14
Journal:
Dalton Trans. 2014 Sep 14;43(34):12943-51
Content:
Novel metabolites of amodiaquine formed by CYP1A1 and CYP1B1: structure elucidation using electrochemistry, mass spectrometry, and NMR.
Authors:
Johansson T, Jurva U, Grönberg G, Weidolf L, Masimirembwa C
Date:
2009-03-03
Journal:
Drug Metab Dispos. 2009 Mar;37(3):571-9.
Content:
Electrochemical generation of electrophilic drug metabolites: characterization of amodiaquine quinoneimine and cysteinyl conjugates by MS, IR, and NMR.
Authors:
Jurva U, Holmén A, Grönberg G, Masimirembwa C, Weidolf L
Date:
2008-04-21
Journal:
Chem Res Toxicol. 2008 Apr;21(4):928-35.
Content:
Genetic variants of drug metabolizing enzymes and drug transporter (ABCB1) as possible biomarkers for adverse drug reactions in an HIV/AIDS cohort in Zimbabwe.
Authors:
Dhoro M, Ngara B, Kadzirange G, Nhachi C, Masimirembwa C
Date:
2013-09-11
Journal:
Curr HIV Res. 2013 Sep;11(6):481-90.
Content:
Evaluation of Herbal Medicines: Value Addition to Traditional Medicines Through Metabolism, Pharmacokinetic and Safety Studies.
Authors:
Thelingwani R, Masimirembwa C.
Date:
2014-10-10
Journal:
Curr Drug Metab. 2014;15(10):942-52
Content:
Prediction of sites under adaptive evolution in cytochrome P450 sequences and their relationship to substrate recognition sites.
Authors:
Zawaira A, Matimba A, Masimirembwa C
Date:
2008-06-18
Journal:
Pharmacogenet Genomics. 2008 Jun;18(6):467-76
Content:
Heterologous expression and kinetic characterization of human cytochromes P-450: validation of a pharmaceutical tool for drug metabolism research
Authors:
CM Masimirembwa, C Otter, M Berg, M Jönsson, B Leidvik, E Jonsson, TB Andersson , 119
Date:
1999-05-05
Journal:
Drug Metabolism and Disposition 27 (10)
Content:
Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.
Authors:
Ongarora DS, Strydom N, Wicht K, Njoroge M, Wiesner L, Egan TJ, Wittlin S, Jurva U, Masimirembwa CM, Chibale K.
Date:
2015-09-01
Journal:
Bioorg Med Chem. 2015 Sep 1;23(17):5419-32.
Content:
Might ART Adherence Estimates Be Improved by Combining Biomarker and Self-Report Data?
Authors:
7. Rhead R, Masimirembwa C, Cooke G, Takaruza A, Nyamukapa C, Mutsimhi C, Gregson S
Date:
2016-12-14
Journal:
PLoS One. 2016 Dec 14;11(12):e0167852. doi: 10.1371/journal.pone.0167852. eCollection 2016.
Content:
CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe.
Authors:
Dhoro M, Zvada S, Ngara B, Nhachi C, Kadzirange G, Chonzi P, Masimirembwa C.
Date:
2015-03-27
Journal:
BMC Pharmacol Toxicol. 2015 Mar 27;16:4.
Content:
Amodiaquine Clearance and Its Metabolism toN-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate
Authors:
XQ Li, A Björkman, TB Andersson, M Ridderström, CM Masimirembwa , 262
Date:
2002-01-02
Journal:
Pharmacology and Experimental Therapeutics 300 (2)
Content:

Amodiaquine (AQ) metabolism to N-desethylamodiaquine (DEAQ) is the principal route of disposition in humans. Using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) we performed studies to identify the CYP isoform(s) involved in the metabolism of AQ. CYP2C8 was the main hepatic isoform that cleared AQ and catalyzed the formation of DEAQ. The extrahepatic P450s, 1A1 and 1B1, also cleared AQ and catalyzed the formation of an unknown metabolite M2. TheKm and Vmaxvalues for AQ N-desethylation were 1.2 μM and 2.6 pmol/min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 μM and 1462 pmol/min/mg of protein for human liver microsomes (HLMs), respectively. Relative contribution of CYP2C8 in the formation of DEAQ was estimated at 100% using the relative activity factor method. Correlation analyses between AQ metabolism and the activities of eight hepatic P450s were made on 10 different HLM samples. Both the formation of DEAQ and the clearance of AQ showed excellent correlations (r2 = 0.98 and 0.95) with 6α-hydroxylation of paclitaxel, a marker substrate for CYP2C8. The inhibition of DEAQ formation by quercetin was competitive withKi values of 1.96 for CYP2C8 and 1.56 μM for HLMs. Docking of AQ into the active site homology models of the CYP2C isoforms showed favorable interactions with CYP2C8, which supported the likelihood of an N-desethylation reaction. These data show that CYP2C8 is the main hepatic isoform responsible for the metabolism of AQ. The specificity, high affinity, and high turnover make AQ desethylation an excellent marker reaction for CYP2C8 activity.

Establishment of a biobank and pharmacogenetics database of African populations.
Authors:
Matimba A, Oluka MN, Ebeshi BU, Sayi J, Bolaji OO, Guantai AN, Masimirembwa CM
Date:
2008-07-08
Journal:
Eur J Hum Genet. 2008 Jul;16(7):780-3.
Content:
The evaluation of CYP2B6 inhibition by artemisinin antimalarials in recombinant enzymes and human liver microsomes.
Authors:
Ericsson T, Masimirembwa C, Abelo A, Ashton M
Date:
2012-04-02
Journal:
Drug Metab Lett. 2012;6(4):247-57
Content:
Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques.
Authors:
Afzelius L, Raubacher F, Karlén A, Jørgensen FS, Andersson TB, Masimirembwa CM, Zamora I
Date:
2004-11-11
Journal:
Drug Metab Dispos. 2004 Nov;32(11):1218-29.
Content:
Physicochemical and drug metabolism characterization of a series of 4-aminoquinoline-3-hydroxypyridin-4-one hybrid molecules with antimalarial activity.
Authors:
Thelingwani R, Bonn B, Chibale K, Masimirembwa C
Date:
2014-10-10
Journal:
Expert Opin Drug Metab Toxicol. 2014 Oct;10(10):1313-24.
Content:
Clinical, Virologic, Immunologic Outcomes and Emerging HIV Drug Resistance Patterns in Children and Adolescents in Public ART Care in Zimbabwe.
Authors:
Makadzange AT, Higgins-Biddle M, Chimukangara B, Birri R, Gordon M, Mahlanza T, McHugh G, van Dijk JH, Bwakura-Dangarembizi M, Ndung'u T, Masimirembwa C, Phelps B, Amzel A, Ojikutu BO, Walker BD, Ndhlovu CE
Date:
2015-12-14
Journal:
PLoS One. 2015 Dec 14;10(12):
Content:
Identification and characterization of reactive metabolites in natural products-driven drug discovery.
Authors:
Njuguna NM, Masimirembwa C, Chibale K
Date:
2012-03-23
Journal:
J Nat Prod. 2012 Mar 23;75(3):507-13.
Content:
Metabolic stability for drug discovery and development
Authors:
CM Masimirembwa, U Bredberg, TB Andersson , 128
Date:
2003-05-05
Journal:
Clinical pharmacokinetics 42 (6),
Content:
A Simple Phosphate-Buffered-Saline-Based Extraction Method Improves Specificity of HIV Viral Load Monitoring Using Dried Blood Spots.
Authors:
4. Makadzange AT, Boyd FK, Chimukangara B, Masimirembwa C, Katzenstein D, Ndhlovu CE
Date:
2017-05-03
Journal:
J Clin Microbiol. 2017 Jul;55(7):2172-2179. doi: 10.1128/JCM.00176-17
Content:
2. Community Based Antiretroviral Treatment in Rural Zimbabwe.
Authors:
Chimukangara B, Manasa J, Mitchell R, Nyabadza G, Katzenstein D, Masimirembwa C
Date:
2016-10-26
Journal:
AIDS Res Hum Retroviruses
Content:
Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: synthesis and pharmacological evaluation.
Authors:
Ongarora DS, Gut J, Rosenthal PJ, Masimirembwa CM, Chibale K
Date:
2012-08-01
Journal:
Bioorg Med Chem Lett. 2012 Aug 1;22(15):5046-5010.
Content:
The molecular basis of CYP2D6-mediated N-dealkylation: balance between metabolic clearance routes and enzyme inhibition.
Authors:
Bonn B, Masimirembwa CM, Aristei Y, Zamora I
Date:
1998-11-02
Journal:
Drug Metab Dispos. 2008 Nov;36(11):2199-210
Content:
Recommendations of the 2006 Human Variome Project meeting.
Authors:
Cotton RG; 2006 Human Variome Project, Appelbe W, Auerbach AD, Becker K, Bodmer W, Boone DJ, Boulyjenkov V, Brahmachari S, Brody L, Brookes A, Brown AF, Byers P, Cantu JM, Cassiman JJ, Claustres M, Concannon P, Cotton RG, den Dunnen JT, Flicek P, Gibbs R, Hall J, Hasler J, Katz M, Kwok PY, Laradi S, Lindblom A, Maglott D, Marsh S, Masimirembwa CM, Minoshima S, de Ramirez AM, Pagon R, Ramesar R, Ravine D, Richards S, Rimoin D, Ring HZ, Scriver CR, Sherry S, Shimizu N, Stein L, Tadmouri GO, Taylor G, Watson M
Date:
2007-04-03
Journal:
Nat Genet. 2007 Apr;39(4):433-6.
Content:
Potent inhibition of CYP1A2 by Frutinone A, an active ingredient of the broad spectrum antimicrobial herbal extract from P. fruticosa.
Authors:
Thelingwani RS, Dhansay K, Smith P, Chibale K, Masimirembwa CM
Date:
2012-10-12
Journal:
Xenobiotica. 2012 Oct;42(10):989-1000.
Content:
Pharmacogenomics of Rosuvastatin: A Glocal (Global+Local) African Perspective and Expert Review on a Statin Drug.
Authors:
Soko ND, Masimirembwa C, Dandara C. OMICS.
Date:
2016-09-20
Journal:
2016 Sep;20(9):498-509. doi: 10.1089/omi.2016.0114.PMID: 27631189
Content:
Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects.
Authors:
Matimba A, Del-Favero J, Van Broeckhoven C, Masimirembwa C
Date:
2009-01-05
Journal:
Hum Genomics. 2009 Jan;3(2):169-90.
Content:
Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors.
Authors:
Afzelius L, Zamora I, Masimirembwa CM, Karlén A, Andersson TB, Mecucci S, Baroni M, Cruciani G.
Date:
2004-02-12
Journal:
J Med Chem. 2004 Feb 12;47(4):907-14.
Content:
Characterisation of artemisinin-chloroquinoline hybrids for potential metabolic liabilities.
Authors:
Thelingwani R, Leandersson C, Bonn B, Smith P, Chibale K, Masimirembwa C
Date:
2015-09-04
Journal:
Xenobiotica. 2015 Sep 4:1-7. [Epub ahead of print] PMID: 26338168
Content:
A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics
Authors:
1. Soko ND, Masimirembwa C, Dandara C
Date:
2019-06-14
Journal:
BMC Res Notes.
Content:
Electrochemical generation of electrophilic drug metabolites: characterization of amodiaquine quinoneimine and cysteinyl conjugates by MS, IR, and NMR.
Authors:
Jurva U, Holmén A, Grönberg G, Masimirembwa C, Weidolf L
Date:
2008-04-21
Journal:
Chem Res Toxicol. 2008 Apr;21(4):928-35.
Content:
Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans.
Authors:
Bapiro TE, Sayi J, Hasler JA, Jande M, Rimoy G, Masselle A, Masimirembwa CM
Date:
2005-11-07
Journal:
Eur J Clin Pharmacol. 2005 Nov;61(10):755-61.
Content:
Influence of CYP3A5*3 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia.
Authors:
Adeagbo BA, Bolaji OO, Olugbade TA, Durosinmi MA, Bolarinwa RA, Masimirembwa C. J Clin
Date:
2016-10-14
Journal:
Pharm Ther. 2016 Oct;41(5):546-51. doi: 10.1111/jcpt.12424. PMID: 27426203
Content:
Biotransformation and biocatalysis: roles and applications in the discovery of antimalarials.
Authors:
Chigorimbo-Murefu NT, Njoroge M, Nzila A, Louw S, Masimirembwa C, Chibale K
Date:
2012-12-04
Journal:
Future Med Chem. 2012 Dec;4(18):2325-36.
Content:
Extracting molecular information from African natural products to facilitate unique African-led drug-discovery efforts.
Authors:
Chibale K, Guantai EM, Masimirembwa C.
Date:
2011-03-03
Journal:
Future Med Chem. 2011 Mar;3(3):257-61
Content:
The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux.
Authors:
Hayeshi R, Masimirembwa C, Mukanganyama S, Ungell AL
Date:
2006-09-29
Journal:
Eur J Pharm Sci. 2006 Sep;29(1):70-81.
Content:
10. Rolling out Efavirenz for HIV Precision Medicine in Africa: Are We Ready for Pharmacovigilance and Tackling Neuropsychiatric Adverse Effects?
Authors:
Masimirembwa C, Dandara C, Leutscher PD
Date:
2016-10-20
Journal:
OMICS. 2016 Oct;20(10):575-580. PMID: 27627692
Content:
Cytochrome P450 pharmacogenetics in African populations: implications for public health.
Authors:
Dandara C, Swart M, Mpeta B, Wonkam A, Masimirembwa C
Date:
2014-06-10
Journal:
Expert Opin Drug Metab Toxicol. 2014 Jun;10(6):769-85.
Content:
High prevalence of the CYP2B6 516G-->T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe.
Authors:
Nyakutira C, Röshammar D, Chigutsa E, Chonzi P, Ashton M, Nhachi C, Masimirembwa C. Eur J
Date:
2008-04-07
Journal:
Clin Pharmacol. 2008 Apr;64(4):357-65.
Content:
Evaluation of human liver slices and reporter gene assays as systems for predicting the cytochrome p450 induction potential of drugs in vivo in humans.
Authors:
Persson KP, Ekehed S, Otter C, Lutz ES, McPheat J, Masimirembwa CM, Andersson TB
Date:
2006-01-23
Journal:
Pharm Res. 2006 Jan;23(1):56-69
Content:
Technological and cost comparison of cytochrome P450 2B6 (516G>T) genotyping methods in routine clinical practice.
Authors:
Dhoro M, Nhachi C , Masimirembwa C. , Dhoro M, Nhachi C , Masimirembwa C. Technological and cost comparison of cytochrome P450 2B6 (516G>T) genotyping methods in routine clinical practice. African Journal of Biotechnology. 2013.12(19): 2706-2710 (DOI: 10.5897/AJB2013.12043)
Date:
2013-01-01
Journal:
African Journal of Biotechnology
Content:
Inhibition of major drug metabolizing CYPs by common herbal medicines used by HIV/AIDS patients in Africa-- implications for herb-drug interactions.
Authors:
Awortwe C, Bouic PJ, Masimirembwa CM, Rosenkranz B
Date:
2014-07-07
Journal:
Drug Metab Lett. 2014 Jul;7(2):83-95.
Content:
High prevalence of the CYP2B6 516G→ T (* 6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe
Authors:
C Nyakutira, D Röshammar, E Chigutsa, P Chonzi, M Ashton, C Nhachi, CM Masimirembwa , 171
Date:
2008-05-05
Journal:
European journal of clinical pharmacology 64 (4)
Content:
A novel mutant variant of the CYP2D6 gene (CYP2D617) common in a black African population: association with diminished debrisoquine hydroxylase activity
Authors:
C MASIMIREMBWA, I PERSSON, L BERTILSSON, J HASLER , 187
Date:
2009-05-05
Journal:
British journal of clinical pharmacology 42 (6)
Content:
Flavin-containing monooxygenase 3 polymorphisms in 13 ethnic populations from Europe, East Asia and sub-Saharan Africa: frequency and linkage analysis.
Authors:
Mao M, Matimba A, Scordo MG, Gunes A, Zengil H, Yasui-Furukori N, Masimirembwa C, Dahl ML
Date:
2009-09-10
Journal:
Pharmacogenomics. 2009 Sep;10(9):1447-55.
Content:

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