Pravastatin pharmacokinetics

Nishizato Y, Ieiri I, Suzuki H, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 2003 73 554—565. 

Kivisto, K.T. and Niemi, M. (2007) Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharmaceutical Research, 24 (2), 239-247. 

OATP-C Pravastatin Pharmacokinetic parameters 15 lower clearance 53... 

The AUC of a single 40-mg dose of pravastatin was increased by 71% in 10 healthy subjects who took itraconazole 200 mg daily for 4 days, although this did not reach statistical significance. In a similar study, the same dosage of itraconazole caused a modest 51% increase in the AUC of pravastatin. In contrast, one study in 104 subjects found that itraconazole had no effect on pravastatin pharmacokinetics. ... 

Cases of acnte rhabdomyolysis have been reported between lovas-tatin and azithromycin, clarithromycin, or erythromycin and between simvastatin and clarithromycin or roxithromycin. Macrolide antibacterials have also been potentially implicated in cases of rhabdomyolysis with atorvastatin and pravastatin. Pharmacokinetic stndies sn est that the macrolides increase the levels of the statins metabolised by CYP3A4 (namely atorvastatin, Iovastatin and simvastatin). 

Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Effect of rifampicin on pravastatin pharmacokinetics in healthy subjects. Br J Clin Pharmacol (2004) 57, 181-7. 

Hatanaka T. Clinical pharmacokinetics of pravastatin mechanisms of pharmacokinetic events. Clin Pharmacokinet 2000 Dec 39(6) 397-412. Review. 

OATP2B1 (old name OATP-B) is expressed at brush-border membranes of intestinal epithelial cells [32], OATP2B1 exhibited pH-sensitive transport activities for various organic anions such as estrone-3-sulfate, dehydroepiandros-terone sulfate, taurocholic acid, pravastatin, and fexofenadine [33], However, further studies are needed to determine the specific physiological and pharmacokinetic contribution of OATP2B1 for intestinal absorption of these compounds. 

K. Maeda, I. Ieiri, K. Yasuda, A. Fujino, H. Fujiwara, K. Otsubo, M. Hirano, T. Watanabe, Y. Kitamura, H. Kusuhara, and Y. Sugiyama. Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 79 427-439 (2006). 

Sugimoto K, Ohmori M, Tsuruoka S, et al. Different effects of St John s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Therapeut 2001 70(6) 518-524. 

Increases in exposure were reported for atorvastatin (84,154), lovastatin (155,156), and simvastatin (85,87,157). GFJ was shown not to have an effect on the pharmacokinetics of pravastatin (84,154). Atorvastatin exhibited a moderate interaction with GFJ regarding the overall exposure. Lovastatin and simvastatin exhibited a strong interaction. Pravastatin could be chosen as an alternative drug if patients want to ensure a lack of interaction. 

Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. Br J Clin Pharmacol 2004 57(4) 448 55. 

The effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of atorvastatin, ceri-vastatin, and pravastatin have been evaluated in an open, randomized, crossover study in 18 healthy subjects who took single doses of atorvastatin 20 mg, cerivastatin 0.8 mg, or pravastatin 40 mg, with and without itraconazole 200 mg (72). Itraconazole markedly raised atorvastatin plasma concentrations (2.5-fold) and produced modest rises in the plasma concentrations of cerivastatin (1.3-fold) and pravastatin (1.5-fold). These results suggest that in patients taking itraconazole, cerivastatin or pravastatin may be preferable to atorvastatin. 

Healthy volunteers were given protease inhibitors and statins, and the authors concluded that simvastatin should be avoided and that atorvastatin could be used with caution in people taking ritonavir and saquinavir (111). Dosage adjustment of pravastatin may be necessary with co-administration of ritonavir and saquinavir. Pravastatin does not alter the pharmacokinetics of nelfinavir, and thus appears to be safe for co-administration. 

Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000 68(4) 391 100. 

The effects of co-administration of diltiazem, a potent inhibitor of CYP3A, on the pharmacokinetics of pravastatin have been evaluated in a randomized study in 10 healthy volunteers (10). Pravastatin is active alone and is not metabolized by CYP3A. Diltiazem did not alter the oral AUC, maximum serum concentration, or half-life of pravastatin. 

The effects of itraconazole 200 mg on the pharmacokinetics of pravastatin have been studied in a randomized, double-blind, crossover study in 10 healthy volunteers (12). Itraconazole slightly increased the AUC and Cmax of pravastatin, but the changes were not statistically significant the half-life was not altered. 

Md.K. Pasha, S. Muzeeb, S.J.S. Basha, D. Shashikumar, R. Mullangi, N.R. Srinivas, Analysis of five HMG-CoA reductase inhibitors—atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies, Biomed. Chromatogr. 20 (2006) 282-293. 

Niemi M, Pasanen MK, Neuvonen PJ. SLCOIBI polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther 2006 80 356-366. 

Maeda K, Ieiri I, Yasuda K, et al. Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 2006 79 427-439. 

Based on their pharmacokinetic profile alone, the safest statins in chronic compensated liver disease and a history of decompensation are prohahly pravastatin and rosnvastatin. However, clinical experience with rosnvastatin in liver disease is lacking, and so it cannot be recommended. In addition, the true rate of post-marketing adverse drug reactions is not yet clear. Pravastatin is therefore the drug of choice in these patients, where treatment is deemed necessary. It should, however, be avoided in acute episodes until liver function or transaminases stabilise/return to normal. 

The hydrophilic statins (pravastatin, rosuvastatin) are only partly metabolised by the liver [1, 17, 19]. Pravastatin is also metabolised in the stomach [26]. The pharmacokinetics of pravastatin have been shown to change in liver disease, despite its dual route (renal and hepatic) of elimination [27]. Nonetheless, it has been used in liver disease and has been suggested as the statin of choice [26]. Liver metabolism is of minor importance in the clearance of rosuvastatin and its pharmacokinetics are not altered by mild to moderate liver impairment. However, the area under the curve (AUC) is increased in severe liver impairment [1]. Clinical experience with rosuvastatin in liver disease is lacking, and it therefore cannot be recommended. 

An example of the former case (drug A behavior) is illustrated in the effect of food on the PK and the PD of pravastatin, a representative statin in the treatment of hyperlipidemia. Although a low-fat, low-cholesterol meal altered the pharmacokinetics of 20-mg pravastatin significantly, no adverse impact on pharmacodynamics... 

From an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, atorvastatin, fluvastatin, pravastatin, and simvastatin were found to affect ciclosporin pharmacokinetics (228). 

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