From the first posting I made on the old "braintalk" I have written that I was convinced that the Lipitor 10 mg/day my husband took for 4 yrs was directly associated with the onset of Parkinson's disease for him (and 4 other individuals with whom I was corresponding at that time). thru 23andme, we discovered **** has a genetic mutation in the SLCO1B1 gene which encodes the transport protein responsible for movement of statins (all statins) into the liver so this class of drugs could be detoxified and metabolized. Serum levels of statins are greatly increased for individuals who posess SNPs in this gene. My husband possesses 3 of the SNPs identified. No research has been undertaken to detrermine what adverse effects are associated with these SNPs other than myalgias and myopathies. No one has looked at neurodegenerative diseases associated with statin use and SLCO1B1 mutations.
references for discussion of impact of SLCO1B1 muation and statin pharmacolinetics
http://www.ncbi.nlm.nih.gov/pubmed/17108811
SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid.
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M.
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
BACKGROUND AND OBJECTIVE: Organic anion transporting polypeptide 1B1 (OATP1B1) is an uptake transporter located at the sinusoidal membrane of human hepatocytes. This study aimed to investigate the effects of genetic polymorphism in the SLCO1B1 gene encoding OATP1B1 on the pharmacokinetics of simvastatin. METHODS: Four healthy volunteers with the homozygous SLCO1B1 c.521CC genotype, 12 with the heterozygous c.521TC genotype and 16 with the homozygous c.521TT genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin (inactive lactone) and its active metabolite simvastatin acid were measured for 12 h. RESULTS:
THE AUCCO-INFINITY OF SIMVASTATIN ACID WAS 120 AND 221% HIGHER IN PARTICIPANTS WITH THE SLCO1B1 c.521CC genotype than in those with the c.521TC and c.521TT (reference) genotypes, respectively (P<0.001).
THE C max OF SIMVASTATIN ACID WAS 162 AND 200% HIGHER IN PARTICIPANTS WITH c.52cc genotype than in those with the c.521TC and c.521TT genotypes (P<0.001)...
CONCLUSIONS:...RAISED PLASMA CONCENTRATIONS OF SIMVASTATIN ACID IN PATIENTS CARRYING THE SLCO1B1 c,521c VARIANT ALLELE MAY ENHANCE THE RISK OF SYSTEMIC ADVERSE EFFECTS DURING SIMVASTATIN TREATMENT.
In addition, reduced uptake of simvastatin acid by OATP1B1 into the liver in patients with the c.521C allele could reduce its cholesterol-lowering efficacy.
PMID: 17108811 [PubMed - indexed for MEDLINE]Pharmacogenetic and genomic
SECOND STUDY:
important numbers:
1)PEAK PLASMA CONCENTRATION: 231% HIGHER THAN CONTROL
2) MEAN AREA UNDER THE PLASMA CONCENTRATION TIME CURVE OF PRAVASTATIN: 110% ABOVE NORMAL CONTROLS
http://www.nature.com/clpt/journal/v...t2006348a.html
Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin*
Michael Igel MD1, Katja A. Arnold PhD1,et a,
1Department of Clinical Pharmacology, University of Bonn, Bonn Germany
Background and Objective: The polymorphism of SLCO1B1 (solute carrier organic anion transporter family, member 1B1), encoding the hepatic uptake transporter organic anion transporting polypeptide 1B1, has been associated with increased pravastatin concentrations in single-dose studies. We have investigated whether this polymorphism influences the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin.
Methods: A prospective, parallel-group study of 16 healthy volunteers, including 8 carriers of an SLCO1B1 variant haplotype and 8 control subjects, was carried out. Pravastatin pharmacokinetics and reduction in total and low-density lipoprotein (LDL) cholesterol concentrations were analyzed after treatment with 40 mg pravastatin daily for 3 weeks.
Results: The mean area under the plasma concentration–time curve of pravastatin was 110% higher (305.0 149.4 ng h/mL [mean SD] versus 144.9 48.2 ng h/mL, P = .012) and the mean peak concentration in plasma was 231% higher (174.5 98.6 ng/mL versus 52.7 22.1 ng/mL, P = .0042) in the SLCO1B1 variant haplotype group than in the control group. Pravastatin significantly reduced the concentrations of total and LDL cholesterol in both groups. The mean percentage reduction in total cholesterol concentration was 13.1% 9.1% and 19.1% 8.3% in the variant and control groups, respectively (P = .19; 95% confidence interval of difference between groups, -15.3% to 3.3%). The mean percentage reduction in LDL cholesterol concentration was 27.7% 8.3% in the variant group and 32.3% 11.2% in the control group (P = .37; 95% confidence interval for difference, -15.1% to 6.0%).
Conclusions: Despite considerably higher plasma pravastatin concentrations in carriers of an SLCO1B1 variant haplotype, there was no significant difference in the lipid-lowering efficacy of pravastatin between the variant haplotype and control groups. However, this pilot study had sufficient statistical power to detect only a large difference in lipid response between the 2 groups. Further clinical studies are warranted to characterize the impact of the SLCO1B1 polymorphism on the lipid response to pravastatin.
ADDITIONAL REFERENCES:
1) reports higher praavstatin levels in 15% European and 1% African-Americans
Ho RH, Choi L, Lee W, et al:Effect of drug transporter genotypes on pravastatindisposition in European and African American participants. Pharmacogenet Genomics 17:647-656, 2007
2)Reports higher AUC atorvaastatin in idividuals with SLCO1b1 who are on atorvasatin
(AUC=measurement of area under the curve is a measurement of how much drug reaches the blood stream in a set period of time, usually 24 hrs)
Pasanen NK, fredrikson H,
Neuvonen PJ, et al., Different effects of SLCO!B! polymorphism on the pharmacokinetics of atorvastatin adn rosuvasatin. Clin Pharmacol Thera 82:726-733, 2006
3)Reports higher AUC of pitavaastatin
Ieiri I, Suwannakul S, Maeda K, et al: SLCO1B1 (OATP1B1, an uptake tansporter)
and ABCG2(an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers Cin Pharmacol Thera 82:541-547, 2007.
(i forget that my husabnd's nickname is not allowed: his given name if Richard.)