Ritonavir

From PubPK

IUPAC Name
1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate
Physicochemical Properties
CAS number	155213-67-5
PubChem	392622
DrugBank	APRD00312
Molecular Formula	C37H48N6O5S2
Molecular Weight (g/mol)	720.94422
logP	3.9
H-Bond Donor	4
H-Bond Acceptor	7
Polar Surface Area (Å2)	146

Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. As a potent inhibitor of CYP3A activity, ritonavir is frequently used to boost the effects of other protease inhibitors.

Contents 1 Trade Names 2 In Vitro Metabolism & Transport 2.1 Metabolism 2.2 Transport 3 Pharmacokinetics 3.1 Summary of Pharmacokinetic Parameters 3.2 Pharmacokinetics in Preclinical Animals 3.3 Pharmacokinetics in Humans 3.3.1 Absorption 3.3.2 Distribution 3.3.3 Metabolism 3.3.4 Excretion 3.4 Factors Influencing Pharmacokinetics 3.4.1 Age 3.4.2 Gender 3.4.3 Ethnicity 3.4.4 Diseases 3.4.5 Formulation 3.4.6 Food 4 Drug Interactions 4.1 Effects on Other Drugs 4.2 Effects by Other Drugs 5 See also 6 External links 7 References

Trade Names

• Norvir

In Vitro Metabolism & Transport

Metabolism

CYP	Substrate	Inhibitor	Inducer	UGT	Substrate	Inhibitor	Inducer
CYP1A1				UGT1A1
CYP1A2				UGT1A3
CYP1B1				UGT1A4
CYP2A6				UGT1A6
CYP2B6		Yes1		UGT1A9
CYP2C8				UGT2A1
CYP2C9				UGT2A2
CYP2C19				UGT2A3
CYP2D6				UGT2B4
CYP2E1				UGT2B7
CYP2J2				UGT2B10
CYP3A4		Yes2,3		UGT2B11
CYP3A5				UGT2B15
CYP3A7				UGT2B17

References: ¹Hesse et al., 2001; ²Eagling et al., 1997; ³von Moltke et al., 2000;

Transport

ABC	Substrate	Inhibitor	Inducer	SLC	Substrate	Inhibitor	Inducer
ABCB1 (MDR1)				SLC10A1 (NTCP)
ABCB4 (MDR3)				SLC10A2 (NTCP2)
ABCB11 (BSEP)				SLC15A1 (PEPT1)
ABCC1 (MRP1)				SLC15A2 (PEPT2)
ABCC2 (MRP2)				SLC16A1 (MCT1)
ABCC3 (MRP3)				SLC16A4 (MCT5)
ABCC4 (MRP4)				SLC22A1 (OCT1)
ABCC5 (MRP5)				SLC22A2 (OCT2)
ABCC6 (MRP6)				SLC22A3 (OCT3)
ABCC10 (MRP7)				SLC22A4 (OCTN1)
ABCC11 (MRP8)				SLC22A5 (OCTN2)
ABCG2 (BCRP)				SLC22A6 (OAT1)
				SLC22A7 (OAT2)
				SLC22A8 (OAT3)
				SLC22A9 (UST3)
				SLC22A11 (OAT4)
				SLC28A3 (CNT3)
				SLCO1A2 (OATP-A)
				SLCO1B1 (OATP-C)
				SLCO1B3 (OATP8)
				SLCO1C1 (OATP-F)
				SLCO2B1 (OATP-B)
				SLCO3A1 (OATP-D)
				SLCO4A1 (OATP-E)
				SLCO4C1 (OATP-H)

References: ¹

Pharmacokinetics

Summary of Pharmacokinetic Parameters

CL_iv: total plasma clearance after iv administration; CL_R: renal clearance of drug from the plasma; Vss: volume of distribution at steady state; t_1/2: elimination half-life; F_oral: oral bioavailability; f_a: fraction of administered dose absorbed; E_G: gut extraction ratio; E_H: hepatic extraction ratio; fu: unbound fraction of drug in plasma; b/p: blood-to-plasma ratio

	Mouse	Rat	Rabbit	Dog	Monkey	Human
CLiv (mL/min/kg)
CLR (mL/min/kg)
Vss (L/kg)
t1/2β (h)
Foral (%)
fa
EG (%)
EH (%)
fu (%)
b/p

References: ¹

Pharmacokinetics in Preclinical Animals

to be updated

Pharmacokinetics in Humans

to be updated

Absorption

to be updated

Distribution

to be updated

Metabolism

to be updated

Excretion

to be updated

Factors Influencing Pharmacokinetics

Age

to be updated

Gender

to be updated

Ethnicity

to be updated

Diseases

to be updated

Formulation

to be updated

Food

to be updated

Drug Interactions

Ritonavir is an inhibitor of CYP2D6. Mean IC50 value for inhibition of bupropion hydroxylation (CYP2D6 index) was 2.2 μM (Hesse et al., 2001). Ritonavir is a highly potent mechanism-based inhibitors of human CYP3A isoforms (von Moltke et al., 2000).

Effects on Other Drugs

• Alfentanil Steady-state ritonavir increased the AUC of iv and oral alfentanil to 4- and 10-fold, respectively (Kharasch et al., 2008b).
• Elvitegravir Ritonavir (after various doses) substantially increased the AUC of orally-administered elvitegravir (Mathias et al., 2009).
• Fexofenadine Acute and steady-state ritonavir increased the AUC of fexofenadine to 2.8- and 1.4-fold, respectively, through the inhibition of P-gp in the gut (Kharasch et al., 2008b).
• Methadone Steady-state ritonavir reduced the AUC of both R-methadone and S-methadone (iv or oral) to 0.5-fold (Kharasch et al., 2008a).
• Midazolam Ritonavir (20-200 mg) substantially increased the AUC of intravenous midazolam (Mathias et al., 2009).
• Sildenafil The concomitant administration of the protease inhibitor ritonavir (500 mg twice daily) substantially increased sildenafil AUC and C_max of 11-fold (95% CI: 9.0, 12.0) and 3.9-fold (95% CI: 3.2, 4.9), respectively (Muirhead et al., 2000).

Effects by Other Drugs

to be updated

See also

• Efavirenz
• Nelfinavir

External links

• DrugBank- Ritonavir
• PubChem - Ritonavir
• RxList - Norvir
• Wikipedia - Ritonavir
• Norvir (manufacturer's website)

References

• Eagling VA, Back DJ, Barry MG (1997) Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir Br J Clin Pharmacol 44:190-4.
• Hesse LM, von Moltke LL, Shader RI and Greenblatt DJ (2001) Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: Potential drug interactions with bupropion Drug Metabolism and Disposition 29:100-102.
• Kharasch E, Bedynek P, Walker A, Whittington D, Hoffer C (2008a) Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: I. Evidence Against CYP3A Mediation of Methadone Clearance Clin Pharmacol Ther 84:497-505.
• Kharasch E, Bedynek P, Walker A, Whittington D, Hoffer C (2008b) Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P-Glycoprotein Activities Clin Pharmacol Ther 84:506-12.
• Mathias AA, West S, Hui J and Kearney BP (2009) Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure Clin Pharmacol Ther 85:64-70.
• Muirhead GJ, Wulff MB, Fielding A, Kleinermans D and Buss N (2000) Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir Br J Clin Pharmacol 50:99-107.
• von Moltke LL, Durol AL, Duan SX and Greenblatt DJ (2000) Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: Comparison with ketoconazole Eur J Clin Pharmacol 56:259-261.