Ritonavir

From Proteopedia

(Difference between revisions)

Current revision

Better Known as: Norvir (Kaletra when used in combination with Lopinavir)

Marketed By: Abbott Laboratories
Major Indication: Human Immunodeficiency Virus Infection
Drug Class: HIV Protease Inhibitor
Date of FDA Approval (Patent Expiration): 1996 (2013)
U.S. 2009 Sales: $310 Million
Importance: It is a powerful HIV Protease inhibitor. It is a major component of most HIV combination therapies because of its potent inhibition capacity of CYP3A4, increasing the bioavailability of other viral inhibitors.
See Pharmaceutical Drugs for more information about other drugs and disorders.

Mechanism of Action

When HIV infects a host, it directs the synthesis of several polyproteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by HIV Protease. The subunits of come together to form a catalytic tunnel capable of binding the nascent peptides and cleaving them into their mature form. Buried within this tunnel lies , which contain the . These catalytic Asp residues carry out the hydrolytic cleavage of the viral polyproteins. Ritonavir to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their functional form, HIV is unable to mature and proliferate, allowing the patients immune system to fight off the infection more easily.^[1]^[2]

Despite its ability to inhibit HIV Protease, Ritonavir is primarily used in combination therapies to inhibit the metabolizing enzyme, (CYP3A4). Ritonair binds with , inhibiting it. Since it is this enzyme which is responsible for metabolizing the other HIV Protease inhibitors, Ritonavir's inhibition of CYP3A4 increases the bioavilaibility of other antiviral medications.^[3]

Drug Resistance

The biggest difficulty with treating HIV is the rapidity at which it mutates and becomes resistant to treatments. To view a comprehensive and interactive analysis of the mutations which confer drug resistance to HIV Protease, See: HIV Protease Inhibitor Resistance Profile

Pharmacokinetics

HIV Protease Inhibitor Pharmacokinetics
Parameter	Ritonavir	Tipranavir	Indinavir	Saquinavir	Amprenavir	Fosamprenavir	Lopinavir	Darunavir	Atazanavir	Nelfinavir
T_max (hr)	4.4	~3	1.5	3.7	.98	1.5-4	2	.5	2-4	3.1
C_max (ng/ml)	13120	14600	8100	2297	4901	4820	11.9	2730	~4393	4701
Bioavailability (%)	--	--	65	4	--	--	--	--	68	20-80
Protein Binding (%)	99	>99	61	98	90	90	99	95	86	98
T_1/2 (hr)	4.8	4.2	1.2	4.5	5.5	7.7	6.1	29.4	5.3	3.3
AUC (ng/ml/hr)	128100	46500	20900	13467	11999	35000	117600	4746	~26045	31906
Clearance (L/h)	~8.4	32.4	49.5	36.7	56.8	84.4	1.7	32.8	13.6	37.3
Dosage (mg)	600	600	800	1000	600	1400	280	400	400	1250
Metabolism	Hepatic (CYP3A4 & CYP2C19)	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Hepatic (CYP3A4 & CYP3A5)	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Hepatic (CYP3A4)

For Pharmacokinetic Data References, See: References

References

↑ Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ. The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie. 1991 Nov;73(11):1391-6. PMID:1799632
↑ Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT. Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. Proteins. 2007 Apr 1;67(1):232-42. PMID:17243183 doi:10.1002/prot.21304
↑ Sevrioukova IF, Poulos TL. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc Natl Acad Sci U S A. 2010 Oct 11. PMID:20937904 doi:10.1073/pnas.1010693107

Proteopedia Page Contributors and Editors (what is this?)

David Canner, Alexander Berchansky, Eric Martz

Retrieved from "http://52.214.119.220/wiki/index.php/Ritonavir"

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 The biggest difficulty with treating [[HIV]] is the rapidity at which it mutates and becomes resistant to treatments. To view a comprehensive and interactive analysis of the mutations which confer drug resistance to [[HIV Protease]], See: [[HIV Protease Inhibitor Resistance Profile]]
 </StructureSection>
+===See Also===
+* The page [[Molecular Playground/HIV Protease Inhibitor]] summarizes the history of AIDS before Ritonavir and the impact of Ritonavir and other [[HIV protease]] inhibitors.
 ===Pharmacokinetics===
 <table style="background: cellspacing="0px"  align="" cellpadding="0px" width="42%">

Ritonavir

From Proteopedia

Current revision

Better Known as: Norvir (Kaletra when used in combination with Lopinavir)

Mechanism of Action

Drug Resistance

See Also

Pharmacokinetics

References

Proteopedia Page Contributors and Editors (what is this?)

Views

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